World Preclinical Congress 2015 Brochure

Final AgendaREGISTER BY MARCH 13 AND SAVE UP TO $400!

WorldPharmaCongress.com

Preclinical Models in Oncology

Imaging in Oncology

Targeting GPCRs

Predicting Drug Toxicity

Blood-Brain Barrier

Mastering Medicinal Chemistry

Chemical Biology for Target Validation

June 10-11Tumor Models for Immunotherapy

3D Cellular Models

Targeting Histone Acetylation

Functional Genomics Technologies

Property-Based Drug Design

Chemical Proteomics for Target Validation

June 11-12

Organized by: Cambridge Healthtech Institute

PREMIER SPONSOR

• 13 conferences covering the hottest topics in preclinical research

• 950+ international delegates focusing on preclinical research and the challenges and opportunities in early drug discovery and development

• 11 short courses offering interactive discussions with experts in the field

• Exclusive training seminar on Applying Pharmacology to New Drug Discovery

• Plenary keynote panel featuring experts talking about the breakthrough drugs in recent years

• Student fellowships bringing together young researchers looking to make a difference

• Expansive exhibit hall showcasing 65+ sponsors & exhibitors

• Dedicated poster viewing, roundtables and panel discussions for active networking

Tackling Translational Challenges

June 10-12, 2015 Westin Boston Waterfront, Boston, MA

WORLD PRECLINICALCONGRESS

14th Annual

EVENT HIGHLIGHTS:

WorldPharmaCongress.com World Preclincial Congress | 2

Tuesday, June 9

Wednesday,June 10

Thursday,June 11

Friday,June 12

Conference-at-a-Glance

Tackling Translational ChallengesThe World Preclinical Congress (WPC; formerly the World Pharma Congress), now in its 14th year, is making a commitment to focus predominantly on preclinical research and highlight the challenges and opportunities in early drug discovery and development. World Preclinical Congress 2015 brings together some of the hottest topics being discussed in the pharma/biotech world and provides a unique forum for scientists and clinicians to exchange ideas and collaborate to overcome some of the translational challenges. This coincides with the event moving to Boston, now a premier hub for preclinical activity and alliances.

Plenary Keynote Panelists:

Clinical Development of Keytruda David Kaufman, M.D., Ph.D., Director/Senior Principal Scientist, Oncology/Immunotherapy Clinical Research, Merck

Discovery of Ivacaftor, an Orally Bioavailable CFTR PotentiatorPeter Grootenhuis, Ph.D., Senior Director, Chemistry, Vertex Pharmaceuticals

Harvoni Drug Development Challenges: The Role of Risk in Rapid DevelopmentPhillip Pang, M.D., Ph.D., Director, Clinical Research, Gilead Sciences

PREMIER SPONSOR CORPORATE SPONSORS

CORPORATE SUPPORT SPONSOR

Dinner Short Courses*

Pre-Conference Short Courses*

Novel Preclinical Models in Oncology

Translational Imaging in Cancer Drug Development

Targeting GPCRs

Blood-Brain Barrier





Targeting GPCRs

Blood-Brain Barrier



Tumor Models for Cancer Immunotherapy

3D Cellular Models


Property-Based Drug Design in Medicinal Chemistry


Tumor Models for Cancer Immunotherapy

3D Cellular Models


Property-Based Drug Design in Medicinal Chemistry


New Models for Predicting Drug Toxicity

New Models for Predicting Drug Toxicity

Synergistic Use of Functional Genomics Technologies


Applying Pharmacology to New Drug Discovery Training Seminar*

Applying Pharmacology to New Drug Discovery Training Seminar*

Plenary Keynote Panel

Plenary Keynote Panel Wednesday, June 10 | 5:00 pm

Our Plenary Keynote Panel this year features senior executives from pharma/biotech who have played an important role in bringing to market some of the most innovative drugs in recent years. They are here to share their stories on what transpired behind-the-scenes, how they could overcome the translational challenges, and what they see as key drivers in making similar breakthroughs going forward.

* Separate registration required.


http://www.worldpharmacongress.com/Cancer-Models/

http://www.worldpharmacongress.com/Translational-Cancer-Imaging/

http://www.worldpharmacongress.com/Targeting-GPCRs/

http://www.worldpharmacongress.com/Blood-Brain-Barrier/

http://www.healthtech.com/medicinal-chemistry/

http://www.healthtech.com/Chemical-Biology/

http://www.worldpharmacongress.com/Cancer-Models/

http://www.worldpharmacongress.com/Translational-Cancer-Imaging/

http://www.worldpharmacongress.com/Targeting-GPCRs/

http://www.worldpharmacongress.com/Blood-Brain-Barrier/

http://www.healthtech.com/medicinal-chemistry/


http://www.worldpharmacongress.com/Tumor-Models-Immunotherapy/

http://www.worldpharmacongress.com/3D-Cellular-Models/

http://www.worldpharmacongress.com/Targeting-Histone-Acetylation/

http://www.healthtech.com/Property-Based-Drug-Design/


http://www.worldpharmacongress.com/Tumor-Models-Immunotherapy/

http://www.worldpharmacongress.com/3D-Cellular-Models/

http://www.worldpharmacongress.com/Targeting-Histone-Acetylation/

http://www.healthtech.com/Property-Based-Drug-Design/


http://www.worldpharmacongress.com/Drug-Safety-Conference/

http://www.worldpharmacongress.com/Drug-Safety-Conference/

http://www.worldpharmacongress.com/Functional-Genomics/

http://www.worldpharmacongress.com/Functional-Genomics/

http://www.worldpharmacongress.com/wpc_content.aspx?id=142975

http://www.worldpharmacongress.com/wpc_content.aspx?id=142975

WorldPharmaCongress.com

Full time graduate students and PhD Candidates are encouraged to apply for the World Preclinical Congress Student Fellowship. Applications are due by March 27, 2015.

SHORT COURSES

Student Fellowship

Hotel & Travel Information

Conference Venue and Host Hotel:

Westin Boston Waterfront

425 Summer St.

Boston, MA 02210

T: 617-532-4600

Room Rate: $299 s/dReservation Cutoff: May 13, 2015

Please visit the hotel and travel page of our website to reserve your sleeping accommodations. You will need to identify yourself as a Cambridge Healthtech Institute conference attendee to receive the discounted room rate with the host hotel. Reservations made after the cut-off date or after the group room block has been filled (whichever comes first) will be accepted on a space-and-rate-availability basis. Rooms are limited, so please book early.

Top Reasons to Stay at the Westin Boston Waterfront Hotel• Just three miles from Boston’s Logan

International Airport

• Complimentary wireless internet access in guest rooms

• A short walk, bus, taxi or train ride to Boston’s historic sites and family attractions

• Minutes from some of Boston’s finest restaurants

• Pet friendly

We understand that you have many choices when making your travel arrangements. Please understand that reserving your room in the CHI room block at the conference hotel allows you to take full advantage of the conference sessions, events and networking opportunities, and ensures that our staff will be available to help should you have any issues with your accommodations.

• Interested students must complete the application for the 2015 Student Fellowship

• Fellows are required to present a scientific poster. A poster title and abstract are due at the time of the application.

• All applications will be reviewed by the scientific review committee and the accepted students will be notified no later than April 3, 2015 if they were accepted for the 2015 Student Fellowship

• Accepted 2015 Student Fellows will receive a discounted conference rate of $195*, which must be paid in full by April 24, 2015. Credit card information is requested at the time of the application and will be charged upon application approval.

• This fellowship is limited to 10 students and is for the Main Conference Only*, June 10-12, 2015.

• All accepted 2015 Student Fellows will be asked to help promote the conference onsite at their college, and throughout their social media networks.

• Students not accepted for the 2015 Student Fellowship, can register at a discounted rate $295*, and will not be required to present a poster

* This discounted rate cannot be combined with any other discounts for this event. Your discounted registration does not grant access to any of the short courses or pre-conference events. It also does not include hotel, travel or meals.

Take advantage of the discounted group rate!

Car Rental Discounts:

Special discount rentals have been established with Hertz for this conference.

• Visit www.hertz.com to make your reservation and use Hertz Convention Number (CV) 04KL0006

• Call Hertz directly at 800-654-3131 and reference our Hertz Convention Number 04KL0006

World Preclincial Congress | 3

http://www.hertz.com


PRESENT A POSTER AND SAVE $50!

Cambridge Healthtech Institute encourages attendees to gain further exposure by sharing their work in the poster sessions. To secure a poster board and inclusion in the conference materials, your abstract must be submitted, approved and your registration paid in full by April 24, 2015.

Register online, or by phone, fax or mail. Please indicate that you would like to present a poster. Once your registration has been fully processed, we will send an email with a unique link and instructions for submitting your abstract using our online abstract submission tool. Please see the website for more details.

COMPANY TYPE

Commercial (Pharma/Biotech) 58%

Academic 24%

Healthcare/Hospital 8%

Government 5%

Services/Societies 4%

Press 1%

GEOGRAPHIC LOCATION

USA* 72%

Europe 14%

Asia 9%

Other 5%

*USA Breakdown:

East Coast 75%

West Coast 14%

Midwest 11%

COMPANY TITLE

Scientist/Technologist 42%

Executive/Director/Manager 31%

Professor 15%

Sales/Marketing 12%

Reasons you should present your research poster at this conference:

• Your poster will be seen by our international delegation, representing leaders from top pharmaceutical, biotech, academic and government institutions

• Receive $50 off your registration

• Your poster abstract will be published in our conference materials

2014 Attendee Demographics

A focused group with a diversified background. The interaction among the attendees was superb.

Senior Principal Scientist, Chemical R&D, Pfizer“ ”


June 9, 2015 | Boston, MA

*SHORT COURSES

Student FellowshipAfternoon Courses | 2:00 – 5:00 pm

Allosteric Modulators of GPCRs, (PAMs NAMs)

The course will provide an overview on allosteric modulation of class A, B and C GPCRs: screening, molecular pharmacology, signal bias, medicinal chemistry and development challenges. For each of these areas, we will cover the theory and best practices while delving into case studies to highlight key challenges and caveats.

Instructors:Craig W. Lindsley, Ph.D., William K. Warren, Jr. Chair in Medicine, Professor of Pharmacology and Chemistry; Director, Medicinal Chemistry; Director, The Vanderbilt Specialized Chemistry Center

Corey Hopkins, Ph.D., Research Assistant Professor, Vanderbilt Center for Neuroscience Drug Discovery

Imaging of Blood-Brain Barrier Function

Topics to be covered:

• Review of structure and function of the BBB and delivering therapeutic agents to specific regions of the brain

• In vitro imaging, both qualitative and quantitative, microscopy and other imaging techniques

• In vivo imaging in animals, both qualitative and quantitative using different imaging modalities, nuclear, ultrasound, MRI and optical

• In vivo imaging in humans, both qualitative and quantitative

Instructors:King C. Li, M.D., FRCP(C), MBA, Senior Associate Dean for Clinical and Translational Research; Professor and Chair, Department of Radiology, Wake Forest School of Medicine

Lawrence Berliner, Ph.D., Professor of Chemistry and Biochemistry, University of Denver; Emeritus, Ohio State University

Drug Metabolism and Its Impact on Decisions in Drug Discovery & Development

This short course will focus on concepts important for those wanting to understand how drug metabolism is applied to drug discovery and development. Topics will include how drugs are metabolized, the enzymes involved and the growing importance of transporters in drug disposition and safety. Those scientists involved in medicinal chemistry, pharmacology and drug metabolism will benefit from this overview.

• Biotransformation and the role of metabolism in drug toxicity

• Strategies to identify drug metabolites

• Enzymes involved in the metabolism of drugs

• Metabolism-based drug-drug interactions

• Transporters relevant for drug uptake and efflux

• Experimental systems to investigate transporters

Instructors:David Stresser, Program Manager, Corning Gentest Contract Research Services

John Erve, Ph.D., DABT, Jerve Scientific Consulting, Inc.

Mingxiang Liao, Ph.D., Senior Scientist I, DMPK, Takeda Pharmaceutical Intl. Company

Dinner Courses | 6:00 – 9:00 pm

Biased GPCR Ligands: Towards Novel Drug Discovery

GPCRs represent the largest class of drug targets in the human genome and about half of the currently marketed drugs work by turning them “on” or “off”. The new paradigm of biased GPCR signaling i.e. activating selective signaling pathways downstream of a GPCR has led to idea of a new class of drugs that are likely to be more effective and have lesser side effects. This concept opens the door for a new generation of drugs and paves the way for utilizing even the current targets with a new perspective.

This course will cover:

• The basic introduction of biased GPCR signaling paradigm and concepts of biased ligands

• How to screen for biased ligands (conventional and emerging approaches and assays)• Case studies of immense therapeutic potential of biased ligands• Examples of biased ligands in clinical trials and their current status• New concepts of ligand bias: approaches for inducing bias from inside the cell Instructor:Arun Shukla, Ph.D., Professor, Department of Biological Sciences and Bioengineering, Indian Institute of Technology and Wellcome Trust/DBT Allicance Intermediate Fellow

Understanding and Dealing with Drug Disposition in CNS


• Enabling faster compound selection in CNS drug discovery by Pharmacokinetics/pharmacodynamics (PK/PD) modeling and simulation.

• Disposition of Biologics: the absorption, distribution and clearance of bio-therapeutics

• Kinetic relationship between systemic circulation and CNS• Understanding Factors that affect Brain ISF/CSF production and clearance and

its implications Onset of CNS diseases Drug – drug interaction Dosing strategy for drugs that may have CNS implications. Instructors:Qin Wang, Ph.D., Principal Scientist, Translational Sciences, Biogen Idec

Margareta Hammarlund-Udenaes, Ph.D., Professor, Translational PK/PD,Department of Pharmaceutical Biosciences, Uppsala University

Navigating the CiPA Landscape Sponsored by

This dinner course will provide an important update on the CiPA (Comprehensive in vitro Proarrhythmia Assay) initiative. Present ICH S7A and S7B guidelines regulate non-clinical testing for cardiovascular safety. The ICH guidelines have focused on QT/QTc intervals and potential arrhythmia. Experience has shown, however, that cardiovascular assessment should include more than the hERG assay and evaluation of other ion channels should be considered for a more comprehensive cardiovascular evaluation. The session will introduce and review these ion channel assays, describe other in vitro assays (i.e., stem cells cardiomyocytes), and in vivo and secondary cardiovascular assays. The current pharmaceutical and regulatory thinking process of cardiovascular evaluation will be discussed, including a proposal of modification/elimination of ICH E14.

Instructors:Bernard Fermini, Ph.D., Associate Research Fellow, Global Safety Pharmacology, Pfizer Global Research & Development

Gary Gintant, Ph.D., Research Fellow, Integrative Pharmacology, Abbvie

Philip Sager, M.D., FACC, FAHA, FHRS, Consulting Professor of Medicine, Stanford University School of Medicine; Chair, Scientific Programs Committee, Cardiac Safety Research Consortium

Thomas J Colatsky, Ph.D., Director, Division of Applied Regulatory Science, OCP/OTS/CDER, US Food and Drug Administration

Imaging in Cancer Research: Key Applications, Modalities and Strategies


• Strengths and Limitations of Imaging Modalities • Imaging Agent Design and Synthesis• Novel Cell-Based Imaging Technologies Instructors:Vania Kenanova, Ph.D., Head, Pre-clinical PET/ SPECT/CT Imaging Laboratory, Global Imaging Group, Novartis Institute for BioMedical Research

Ned Kirkpatrick, Ph.D., Investigator I, Global Imaging Group, ASI, Novartis Institute for BioMedical Research

Quang-Dé Nguyen, Ph.D., Director of the Lurie Family Imaging Center, Senior Scientist, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute

Additional Instructors to be Announced



MEDIA PARTNERS

*SHORT COURSES

Student Fellowship

June 11, 2015 | Boston, MA

Dinner Courses | 7:00 – 10:00 pm

Optimizing Physical Properties of Molecules to Achieve High-Quality Clinical Candidates

Topics to be discussed:

• Determination, Evaluation and use of physical properties in drug discover

• Discussion of properties such as solubility, ligand efficiency, log P, crystallizations, and solubility

• Experimental best practices and case studies

Instructor:

Terry Richard Stouch, Ph.D., President, Science for Solutions, LLC

How to Best Utilize Organotypic 3D Cell Cultures in Oncology

The course will provide an overview of the various 3D cell culture models available, their strengths and weaknesses, and where and how these models are being used, specifically for oncology research. The instructors will share their experiences on how they tested and evaluated various cell culture reagents and growth matrices, what worked and what didn’t and what you need to consider when setting up low and high throughput screening experiments using 3D cell cultures in your lab. The challenges working with 3D cell cultures, from experimental design to data analysis will be discussed.

Instructors:

Arvind Rao, Ph.D., Assistant Professor, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center

Geoffrey A. Bartholomeusz, Ph.D., Associate Professor and Director of the siRNA Core Facility, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

Sophie Lelièvre, D.V.M., LLM, Ph.D., Professor, Department of Basic Medical Sciences; Associate Director, Collaborative Science, NCI-Designated Purdue Center for Cancer Research, Purdue University

3D Printing

The promise of 3D bioprinting to create human tissues layer by layer is immense. Creating viable 3D screening models can lead to more effective drug development and more accurate drug testing. However, organ and tissue structures vary in complexity, and printing with living cells is complicated.


• 3D Printer Platforms: Inkjet vs. Pressurized Printing

• 3D Modeling (CAT Scans, Laser Scans and CAD)

• Scaffold Selection

• Cell Source Selection

• Bioinks

• Vascularization

This dinner course is designed for biological researchers who are interested in learning more about 3D bioprinting, applying it to building a living tissue or organ of their choice and understanding the potential role in pharmaceutical drug research.

Instructors:

Michael Drues, Ph.D., President, Vascular Sciences

David Kolesky, Research Scientist, Jennifer Lewis Laboratory, School of Engineering and Applied Sciences and Wyss Institute for Biologically Inspired Engineering, Harvard University


PDX Models Update


• PDX technology: core principles and latest advances

• Major applications including novel ones such as, circulating tumor cell-derived PDX advancements

• PDX models to study the immune response of cancer patients to their tumors, and others

• Utilizing data to inform clinical decisions

Instructors:

Richard B. Bankert, V.M.D., Ph.D., Professor, Department of Microbiology and Immunology, State University of New York at Buffalo

Neal Goodwin, Ph.D., Vice President Corporate Research Development Champions Oncology, Inc.



OFFICIAL MEDIA SPONSOR SPONSORING ORGANIZATION LEAD SPONSORING PUBLICATIONS

SPONSORING PUBLICATIONS

WEB PARTNERS MEDIA PARTNERS

Course Outline1. Assay Formats/Experimental Design

a. Binding b. Functional Assays c. Null Method Assays

2. Agonism a. Agonist Affinity/Efficacy b. Black/Leff Operational model

3. Biased Signaling (Agonism)

a. Mechanism of Biased Signaling b. Quantifying Biased Agonism c. Therapeutic application(s)

4. Orthosteric Antagonism (I) a. Competitive b. Non-Competitive/Irreversible

5. Orthosteric Antagonism (II)a. Partial Agonismb. Inverse Agonism

6. Allosteric Modulation (I)a. Functional Allosteric Modelb. Negative Allosteric Modulators (NAMs)

7. Allosteric Modulation (II)a. Positive Allosteric Modulators (PAMs)b. Allosteric Agonism

8. Drug-Receptor Kineticsa. Measuring Target Coverageb. Allosteric Proof-of-Conceptc. Application of Real-Time Kinetics

9. Drug Screeninga. Design of Screening Assaysb. Screening for Allosteric Modulators

June 11-12, 2015 | Boston, MA

Thursday, June 11 | 2:00 - 6:30 pm

Friday, June 12 | 8:00 am - 3:30 pm

Over the past 6 six years, the primary cause of new drug candidate failures (50%) has been failure of therapeutic efficacy. Put another way, drug discovery programs do everything right, get the defined candidate molecule, only to have it fail in therapeutic trials. Among the most prevalent reasons proposed for this shortcoming is the lack of translation of in vitro and recombinant drug activity to therapeutic in vivo whole systems. Drug activity in complete systems can be characterized with the application of pharmacological principles which translate drug behaviors in various organs with molecular scales of affinity and efficacy.Pharmacological techniques are unique in that they can convert descriptive data (what we see, potency, activity in a given system) to predictive data (molecular scales of activity that can be used to predict activity in all systems including the therapeutic one, i.e. affinity, efficacy). The predicted outcome of this process is a far lower failure rate as molecules are progressed toward clinical testing.

This course will describe pharmacological principles and procedures to quantify affinity, efficacy, biased signaling and allostery to better screen for new drugs and characterize drug candidates in lead optimization assays.

Instructor: Terry Kenakin presently is a Professor of Pharmacology in the Dept of Pharmacology, University of North Carolina School of Medicine. The course is taught from the perspective of industrial drug discovery; Dr. Kenakin has worked in drug industry for 32 years (7 at Burroughs-Wellcome, RTP, NC and 25 at GlaxoSmithKline, RTP. NC). He is Editor-in-Chief of the Journal of Receptors and Signal Transduc-tion and Co-Editor-in-Chief of Current Opinion in Pharmacology and is

on numerous journal Editorial Boards. In addition, he has authored over 200 peer reviewed papers and reviews and has written 10 books on Pharmacology.

Course Material: Summary sheets, exercises with answers, relevant papers are included as well as a pdf of allslides. The course is based on the book A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery. 4th Edition, Elsevier/Academic Press, 2014. The table of contents of this book can be viewed here.


Applying Pharmacology to New Drug Discovery The System-Independent Quantification of Molecular Drug Properties for Prediction of Therapeutic Utility

http://www.amazon.com/Pharmacology‐Primer‐Fourth‐Edition‐ Techniques/dp/0124076637/ref=sr_1_1?ie=UTF8&qid=1404150228&sr=8-1&keywords=kenakin#reader_0124076637 .21.0.114&doi=2014-11-26&psv=&pt=tb



4th Annual

PDX and Other Models to Inform Clinical Trials and Guide Patient Care


Suggested Event Package:June 10-11: Novel Preclinical Models in Oncology ConferenceJune 11-12: Tumor Models for Cancer Immunotherapy ConferenceJune 11 Dinner Short Course*: PDX Models Update* Separate registration required.

Conferences Dedicated to Preclinical Models in Oncology at World Preclinical Congress 2015

June 10-11


Imaging in Oncology

June 11-12

Tumor Models for Immunotherapy

3D Cellular Models

WEDNESDAY, JUNE 10

7:00 am Registration and Morning Coffee

MODELING FOR CANCER GENOMIC MEDICINE7:55 Chairperson’s Opening Remarks«

8:00 KEYNOTE PRESENTATION: ENGINEERING THE CANCER GENOMETyler Jacks, Ph.D., Koch Institute for Integrative Cancer Research at MIT

8:30 Session Break

8:35 Preclinical Models Uncover a Novel Notch Mutant Oncogenic Driver Class in Triple Negative Breast Cancer Sensitive to a Gamma Secretase InhibitorPeter Olson, Ph.D., Senior Principal Scientist, Pfizer PharmaceuticalsWhile the Notch pathway is reportedly activated in breast cancer, the molecular mechanisms leading to hyperactivation are poorly understood. To identify predictive biomarkers for the gamma secretase inhibitor PF-03084014, we sequenced sensitive PDX models and mined The Cancer Genome Atlas. We uncovered a disparate array of alterations in the extracellular and PEST domains in multiple Notch receptors that activated the pathway and were sensitive to drug. These data define a new oncogenic driver class that may respond to Notch targeted therapies.

9:05 Patient Derived Xenograft Clinical Trial Program Sponsored by

Neal Goodwin, Ph.D., Director, Corporate Research Development, Champions Oncology

A PDX clinical program to guide patient treatment has engrafted >750 patient specimens with a 70% patient tumor take rate and a >80% correlative treatment accuracy in completed clinical tests. This program has been expanded to support predictive clinical trials for breast, sarcoma, and lung cancers in partnership with clinical trial centers and cooperative trial groups. Ultimately, this program will include matched patient translational studies across numerous patient models for Phase II trial patient stratification.

9:35 Next-Generation Genetically Engineered Cancer ModelsProfessor Dieter Saur, M.D., Consultant and Senior Group Leader, Technische Universität München (TUM), School of Medicine

We generated an inducible dual-recombinase based PDAC model that permits spatial and temporal control of gene expression. This tool provides unparalleled access to the native biology of cancer cells and their hosting stroma, and rigorous genetic validation of candidate therapeutic targets. We performed tumor cell-autonomous and non-autonomous targeting, uncovered hallmarks of human multistep carcinogenesis, validated genetic tumor therapy, and showed that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are in fact dispensable for tumor formation.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing

ANALYSING AND LEVERAGING RESULTS10:50 Statistical Analysis of PDX Studies and Preclinical Phase-II-Like Trials (PP2T) at EMD SeronoAnderson Clark, Ph.D., Director, In vivo Pharmacology, Oncology, EMD Serono Research & Development InstituteAt EMD Serono, we use PDX models in Preclinical Phase 2-Like Trials (PP2T) to support Phase 2 clinical decisions for which the use of statistics has become paramount. Working closely with clinical biostatisticians, we have developed statistical approaches to different aspects of the trials which will be discussed, such as trial design, relationships between preclinical responses and RECIST criteria, responses and how to measure them, and determining treatment differences.

11:20 The Art of the Cocktail: Optimizing Multidrug Combinations in Preclinical StudiesArijit Chakravarty, Ph.D., Director, Modeling & Simulation (DMPK), Takeda Pharmaceutical International Co.The design of optimal combinations relies on maximizing combination efficacy for a given toxicity budget. This presentation will describe the development of novel mathematical modeling methods (based on tricks used by bartenders to develop recreational cocktails), to visualize and design efficient studies for two-drug (and higher-order) combinations, and their application in a practical drug development context, showing their impact on actual study design, and validation with in vivo datasets.

11:50 Evaluating Efficacy Coupled with Toxicity in Sponsored by

a Preclinical Model of Head and Neck Cancer Maria L. Mancini, Ph.D., Associate Director Research, Biomodels, LLCChemoradiation used for the treatment of HNC results in regimen- related mucosal toxicity (mucositis) which impedes optimum cancer therapy and causes significant physiologic and resource adversities. We present a new, highly translational animal model which simultaneously assesses both the targeted efficacy of new anti-tumor agents and their impact on mucositis.

12:05 Sponsored Presentation (Opportunity Available)

12:20 pm LUNCHEON PRESENTATION: Sponsored by 2nd Generation PDX Models Can Help the Progression of Precision MedicineJean-François Mirjolet, Ph.D., Technology Director, OncodesignPanels of PDX models reflecting the genetic diversity of human cancers can increase the predictivity of patients’ tumor response to treatments. But there is still a critical need for better predictive models for novel agents targeting the tumor microenvironment. In addition to the well characterized syngeneic models used for immuno-oncology drug testing, Oncodesign developed highly refined PDX models in microenvironment-humanized mice, demonstrating usefulness in PDX tumor dissemination and immuno-oncology research.

1:00 Refreshment Break in the Exhibit Hall with Poster Viewing


Novel Preclinical Models in Oncology4th Annual June 10-11, 2015 | Boston, MA

IMAGING ADVANCES AND END POINTS IN CANCER RESEARCH

1:30 Chairperson’s Remarks

1:35 Translational Imaging in OncologyDaniel P. Bradley, Ph.D., Head, Biomedical Imaging, Takeda Boston, Takeda Pharmaceuticals International Co.Daniel will present on a number of programs that he has directly worked on, or working on, that have been developed in translational imaging in oncology. Importantly, this talk will highlight important lessons learned about collaboration, timing, perspectives and science with a hope that other groups in the imaging community can leverage this information for future developments. The Biomedical Imaging Group balances its portfolio between the use of conventional imaging biomarkers used in a novel biological and/or pharmacological context to advanced imaging techniques.

2:05 Non-Invasive and Simultaneous Measurement of Pharmacokinetics and Pharmacodynamics in Preclinical Cancer ModelsWerner Scheuer, Research Leader, Pharma Research and Early Development, Discovery Oncology, Roche Diagnostics GmbHNon-invasive imaging modalities (optical and micro-computed tomography) in combination with ex vivo analysis (3D-multispectral fluorescence microscopy, FACS) are an undispensable tool to assess the anti-tumoral efficacy of new compounds. Proliferation of tumor cells, metastasis, angiogenesis, and induction of apoptosis as well as phosphorylation of kinases can be monitored in mice carrying tumor cells s.c. or orthotopically. The quantification of these pharmacodynamics (Pd) read-outs are combined with optical pharmacokinetics (Pk). The simultaneous measurement of Pd and Pk reduces the number of animals significantly and provides a comprehensive evaluation of new drugs.

2:35 Normalizing Tumor Microvasculature and MicroenvironmentDai Fukumura, M.D., Ph.D., Deputy Director, Edwin L. Steele Laboratory; Biologist, Department of Radiation Oncology, Massachusetts General Hospital; Associate Professor, Harvard Medical SchoolIntravital microscopy techniques and sophisticated animal models have been providing unprecedented molecular, cellular, anatomical and functional insights in tumor biology. Tumor microvasculature is structurally and functionally abnormal hindering drug delivery and inducing a hostile microenvironment that causes ineffectiveness of anti-tumor treatments. Imbalance of pro- and anti-angiogenic factors is causing these pathophysiological features in the tumor. Hence, restoring the balance of these factors in tumors may “normalize” tumor vasculature, improve its function and microenvironment, and enhance the efficacy of cytotoxic therapies.

3:05 Development of Companion Diagnostics: An Imaging ApproachSusanta Sarkar, Ph.D., Director, Translational/Clinical Imaging, Sanofi OncologyDevelopment of companion diagnostics will improve the benefit to risk ratio of a given therapy and thus will help reduce drug development costs significantly. A molecular imaging approach allows noninvasive assessment of target expression and its interaction with drugs in situ. This presentation will elaborate on these approaches for the successful development of imaging based companion diagnostics.

3:35 Presentation to be Announced Sponsored by



»5:00 PLENARY KEYNOTE PANEL (see page 2 for details)

6:00 Welcome Reception in the Exhibit Hall with Poster Viewing

7:00 Close of Day

THURSDAY, JUNE 11

7:30 am Interactive Breakout Discussion Groups Each discussion group in this session is led by a moderator/s who ensures focused conversations around key issues. Attendees join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Topics for discussion will be made available on the conference website.

MODELING CANCER HETEROGENEITY8:35 Chairperson’s Remarks

8:45 Modeling Tumor Cell Dormancy in the MouseJeffrey E. Green, M.D., Chief, Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer InstituteAlthough dissemination of tumor cells often occurs at early stages of cancer, clinical recurrence as metastatic disease may not become manifest until many years later following a period of tumor cell dormancy. Modeling the process of tumor dormancy is critical for understanding mechanisms governing late tumor recurrence and translating this knowledge into potential therapeutic or preventive strategies. Recent advances in studying tumor dormancy and potential translational approaches to improve survival will be presented.

9:15 Applications of CRISPR-Cas9 for in vivo Genome EditingRandall Platt, Biological Engineering, MIT, Laboratory of Feng ZhangCRISPR-Cas9 is a versatile genome editing technology for studying the function of genetic elements. To broadly enable the application of Cas9 in vivo, we established a Cre-dependent Cas9 knockin mouse and demonstrated genome editing using adeno-associated virus (AAV)-, lentivirus-, or particle-mediated delivery of guide RNA in neurons, immune cells and endothelial cells. These genome editing strategies empower a wide range of biological and disease modeling applications.

9:45 Dual Wnt and EGFR-MAPK Dependency of BRAFV600E-Mutant Colorectal CancerYouzhen Wang, Ph.D., Principal Scientist, Novartis Institutes for BioMedical ResearchAberrant Wnt pathway activation due to inactivating mutations of RNF43 may contribute to the unresponsiveness of BRAFV600E colorectal cancer (CRC) to BRAF inhibitors. To determine if RNF43 mutations confer Wnt dependency in BRAFV600E CRC, we tested three BRAFV600E;RNF43-mutant CRC PDX models with the porcupine inhibitor WNT974, antagonist of Wnt signaling. We found the triple combination of WNT974+LGX818+cetuximab were efficacious in all three models, which suggest the Wnt and EGFR-MAPK pathways may jointly promote tumorigenesis of BRAFV600E-mutant CRC.



11:30 Preclinical Models for Precision Medicine in Metastatic Colorectal Cancer: Challenges and OpportunitiesLivio Trusolino, M.D., Ph.D. Associate Professor, Department of Oncological Sciences, University of Torino School of Medicine, Laboratory of Molecular Pharmacology, IRCC, Institute for Cancer Research and TreatmentOur objective is to unravel the signaling pathways and genomic makeups that mediate responsiveness to anticancer therapies, with an emphasis on colorectal cancer. To this aim, we use different technological platforms (phosphoproteomics, next-gen DNA/RNA sequencing) and experimental settings (patient-derived tumorgrafts and patient-derived cancer cell lines). Our pipeline involves the integration of large-scale data for discovery, followed by cell-based mechanistic insight and validation in animal models. This knowledge will form a predictive basis for the rational identification of novel tumor targets.

12:00 pm PANEL DISCUSSION: Modeling and Researching Cancer MetastasisModerator: Bruce R. Zetter, Ph.D., Charles Nowiszewski Professor of Cancer Biology, Department of Surgery, Harvard Medical SchoolPanelists: Speakers of the Day

12:30 Close of Conference


2nd Annual


Suggested Event Package:June 10-11: Novel Preclinical Models in Oncology Conference

June 11-12: Tumor Models for Cancer Immunotherapy Conference

June 11 Dinner Short Course*: PDX Models Update* Separate registration required.


June 10-11


Imaging in Oncology

June 11-12


3D Cellular Models

THURSDAY, JUNE 11

12:00 pm Registration

TRANSLATIONAL IMMUNO-ONCOLOGY2:00 Chairperson’s Opening Remarks

2:05 Preclinical Tumor Models for Evaluating Bispecific Redirected T Cell TherapeuticsChad May, Ph.D., Director, Oncology Research Unit, PfizerStrong evidence exists supporting the important role T-cells play in the immune response against tumors. Still, the ability to initiate tumor specific immune responses remains a challenge. We have developed a bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of tumors expressing target antigens.

2:35 Joint Presentation: Preclinical to Clinical Translation of Anti-PD-1 BlockadeDavid Kaufman, M.D., Ph.D., Director/Senior Principal Scientist, Oncology/Immunotherapy Clinical Research, MerckElaine Pinheiro, Ph.D., Associate Principal Scientist, In vivo Pharmacology – Oncology, Merck Research LaboratoriesKeytruda® (pembrolizumab), a PD-1-specific monoclonal antibody, is approved in the U.S. for advanced melanoma, and is being studied in >30 cancers. We have generated a murine surrogate antibody (muDX400) and determined mechanistic features of PD-1 inhibition in preclinical tumor models. Gene and protein expression signatures reveal determinants of response and resistance. In addition, muDX400 has been combined with chemotherapies, targeted therapies, and other immunotherapies, and the systemic and intratumoral immune landscape has been evaluated. These data will facilitate the clinical development of both pembrolizumab monotherapy and combination therapies. In particular, these data will support the development of novel mechanistic biomarkers that will aid in the customization of immunotherapeutic regimens, elucidation of novel determinants of response, and identification of early indicators of on-treatment response. In turn, data from clinical trials can be used to improve the predictive power of the nonclinical workstream and speed the preclinical development of novel immunotherapeutic agents.

3:35 Presentation to be AnnouncedSponsored by


4:45 Translational Approaches to Preclinical Evaluation of Immune Oncology AgentsBrett Hall, Ph.D., Senior Director & Head, Translational Medicine-Oncology, MedImmuneAn expanding body of basic and translational research has established a solid framework for how the tumor microenvironment (TME) influences cancer biology. The TME influences tumor immune recognition as well as metabolic activity, tumor survival, genomic instability, epigenetic state, metastatic progression, tumor proliferation and therapeutic resistance. For effective clinical translation of immune mediated therapies, it is essential that preclinical models adequately address key immuno-modulatory aspects of the human TME.

ENHANCING IMMUNE RESPONSE

5:15 Adoptive Immunotherapy of Cancer Using ex vivo Expanded Vg9Vd2 T CellsJohn Maher, M.D., Ph.D., Senior Lecturer in Immunology, NIHR Biomedical, Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College LondonVg9Vd2 T-cells recognize phosphoantigen intermediates of mevalonate metabolism and thereby play an important role in tumor immunosurveillance. We have developed systems to expand these cells ex-vivo by over 2000-fold in 2 weeks, enhancing the feasibility of clinical immunotherapy using this approach. Expanded cells exhibit potent anti-tumor activity in xenograft models of ovarian cancer and acute myeloid leukemia in a manner that is potentiated by either free or liposome-encapsulated aminobisphosphonates.

5:45 Enhancing Immune Response to DC/Tumor Fusion Cell Vaccination for the Treatment of Hematologic MalignanciesJacalyn Rosenblatt, M.D., Assistant Professor, Department of Medicine, Harvard Medical SchoolDC/tumor fusion cell vaccination has demonstrated potent immune responses, and clinical responses in a subset of patients. Strategies to augment immune response to vaccination depend on overcoming the immunosuppressive milieu characteristic of patients with malignancy. Combining vaccination with checkpoint blockade and immunomodulatory drugs are being evalauted in clinical trials. In pre-clinical models, we have demonstrated that MUC1 plays a critical role in mediating immune tolerance. Strategies to block MUC1 mediated signalling are being evaluated as a means of augmenting response to immunotherapy.

6:15 Close of Day

FRIDAY, JUNE 12


Tumor Models for Cancer ImmunotherapyAssessing Antitumor Activity and Safety of Immunotherapy Programs


Tumor Models for Cancer Immunotherapy2nd Annual


DESIGNING AND ASSESSING COMBINATIONS8:35 Chairperson’s Remarks

8:45 Identification of Novel Immune-Modulatory Combination though Transcriptomic and Proteomic-Based Analysis of Tumor ModelsDaniela Cipolletta, Ph.D., Research Investigator, Clinical Translational Oncology, TCO, Novartis OncologyWe have used transcriptomic and proteomic approaches to monitor the immune response following perturbation of key onco-pathway and immune-checkpoint nodes in preclinical tumor models. This approach has enabled our understanding of tumor induced immune modulation and the identification of novel combinatorial strategies in specific cancer settings

9:15 Combining Radiation Therapy and Cancer Immunotherapy: Preclinical Assessment and Translational ApproachesMaria Angelica Cortez, Ph.D., Postdoctoral Fellow, Experimental Radiation Oncology, UT MD Anderson Cancer CenterThe immune-modulating effects of radiation therapy have recently gained considerable interest and there have been multiple reports of synergy between radiation and immunotherapy. However, additional pre-clinical studies are needed to demonstrate the antigen-specific nature of radiation induced immune responses and elucidate potential mechanisms of synergy withimmunotherapy. Here we demonstrate the ability of stereotactic radiotherapy to induce endogenous antigen-specific immune responses when combined with anti-PD-1 checkpoint blockade immunotherapy.

9:45 Personalized Mouse Model for Preclinical Testing

Sponsored byof Drugs Targeting Immune Checkpoints

Keren Paz, Ph.D., CSO, Champions OncologyThe blockade of immune checkpoints is a promising therapeutic avenue for cancer therapy, with durable objective responses observed in patients with various solid tumors. However, current animal models often fail to accurately identify immunotherapies with the greatest clinical potential and there exists a need for reliable preclinical tools to test these drugs directly against human cancers. To circumvent this limitation, Champions Oncology has developed the ImmunoGraft, whereby two innovative technologies, the Champions TumorGraft (a type of patient-derived xenograft) and humanized mice (immunodeficient mice reconstituted with a human immune system), are combined in a single platform.


11:00 Developing and Deploying Novel Experimental Model Systems in Ovarian Cancer for Improved Drug DiscoveryRonny I. Drapkin, M.D., Ph.D., Director, Ovarian Cancer Research Center, Perelman School of Medicine, University of PennsylvaniaThe emergence of the fallopian tube as a dominant site of origin for high-grade serous ovarian carcinomas has sparked the development of novel model systems, including PDX and GEM models, that are impacting development of novel drug therapies, methods for early detection and approaches to chemo- and immuno-prevention. Examples of how these models are being integrated to address key clinical issues will be discussed.

11:30 A Rapid Establishment of Patient Derived Tumor Xenograft Microenvironments that Enable Preclinical Evaluations of Chemo-Immune Therapeutic StrategiesRichard B. Bankert, V.M.D., Ph.D., Professor, Department of Microbiology and Immunology, State University of NY at Buffalo, School of Medicine and Biomedical SciencesWe report here a simple and reliable model system in which ovarian tumor cell aggregates implanted intraperitoneally into severely immunodeficient NSG mice establish tumor microenvironments within the omentum within one week. The rapid establishment of tumor xenografts within this small anatomically well-defined site enables the recovery, characterization, and quantification of tumor and tumor-associated T cells.

12:00 pm PANEL DISCUSSION: Designing and Assessing CombinationsPanelists: Speakers of the Session


12:45 LUNCHEON PRESENTATION: Humanized Immune System Mice for Immuno-Oncology Applications

Sponsored by

Leon L. Hall, Ph.D., Senior Director, Global Scientific Development and Translational Discovery Services, Taconic Biosciences, Inc. Mouse models are widely used in preclinical oncology research but species differences can limit efficacy predictions for clinical translation. Taconic Biosciences’ Immune system humanization program is being leveraged to accelerate efficacy and safety testing of novel immunotherapies. An overview of Taconic’s humanization program will include data showing the utility of humanized mice in PDX applications for immuno-oncology drug development. Additionally, recent advances utilizing next generation humanized mice will be presented.

1:30 Session Break

TOOLS AND TECHNOLOGIES2:00 Chairperson’s Remarks

2:05 Genetic Engineering of the Mouse Immune System to Test Novel Cancer Immuno-TherapueticsGavin Thurston, Ph.D., Vice President, Oncology & Angiogenesis Research, Regeneron PharmaceuticalsOne of the challenges in developing clinical immuno-therapeutics is testing these agents in relevant preclinical tumor models. A particular issue has been the lack of cross-reactivity of human-specific therapeutic monoclonal antibodies to murine targets. We have used VelociGene® technology to humanize a variety of targets within the immune system, allowing us to test and compare novel immuno-therapeutics. Examples will be provided for immune modulatory antibodies and bispecific antibodies.

2:35 ImmunoPET Imaging in the Development of Therapeutic AntibodiesJan Marik, Ph.D., Department of Biomedical Imaging, Genentech, Inc.Positron emission tomography with radiolabeled monoclonal antibodies (ImmunoPET) is becoming a valuable tool in translational development of therapeutic antibodies. The half-life of positron emitting radionuclide 89Zr (3.3d) matches well the pharmacokinetics of monoclonal antibodies (mAb) hence good quality images can be obtained and inform about the biodistribution of the drug and/or the targeted antigen. Examples of pre-clinical and clinical use of 89Zr-mAbs in the development of targeted cancer therapeutics will be discussed.

3:05 Imaging the Immune Response to CancerMichael Dougan, M.D., Ph.D., Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer InstituteAppropriate surrogate endpoints for monitoring immune therapy to cancer are currently lacking. My talk will cover work we are doing in the lab to use single domain camelid derived antibodies conjugated to radioisotypes to image the response to anti-cancer immune therapy by positron emission tomography. We envision this strategy as potentially providing a novel means for tracking immune therapies for cancer, with the potential to guide therapy as well as assist in the generation of new treatment.




6th Annual

Novel Imaging Probes and Technologies in Oncology


Suggested Event Package:June 9 Dinner Short Course*: Imaging in Cancer Research

June 10-11: Translational Imaging in Cancer Drug Development Conference

June 11-12: Tumor Models for Cancer Immunotherapy Conference* Separate registration required.


June 10-11


Imaging in Oncology

June 11-12


3D Cellular Models

WEDNESDAY, JUNE 10


TRANSLATIONAL IMAGING IN ONCOLOGY7:55 Chairperson’s Opening Remarks

»8:00 KEYNOTE PRESENTATION: ENGINEERING THE CANCER GENOME

Tyler Jacks, Ph.D., Koch Institute for Integrative Cancer Research at MIT

8:30 Session Break

8:35 Improving Decision Making For Drug Discovery and Early Development In Oncology With ImagingPaul McCracken, Ph.D., Director of Imaging, Biomarkers and Personalized Medicine CFU, EisaiDue to high cost and low probability of success, the pharmaceutical industry needs to improve the decision making process for compounds entering Phase I, better using Phase I studies for decision making beyond safety, and improving the quality of compounds entering clinical trials. Imaging biomarkers can significantly contribute to the decision making process, such as supporting target engagement, proof of concept, drug safety, patient selection, and dose selection.

9:05 Enabling Translational Cancer Research and Drug Development Through The Integration Of Preclinical ImagingQuang-Dé Nguyen, Ph.D., Director of the Lurie Family Imaging Center, Senior Scientist, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer InstituteThe Lurie Family Imaging Center (LFIC), the preclinical arm of the Center for Biomedical Imaging in Oncology (CBIO) at the Dana-Farber Cancer Institute, is a state-of-the-art imaging facility that conducts interdisciplinary in vivo translational and experimental therapeutics studies focused on cancer, with an emphasis on assessment of novel cancer therapeutics, multimodality imaging of cancer, molecular imaging of pharmacodynamic efficacy, development of novel probes, and target validation.

9:35 Click-mediated Therapy for HER2-positive Breast Cancer Dmitri Artemov, Ph.D., Associate Professor Departments of Radiology and Oncology , The Johns Hopkins University School of MedicineTreatment of HER2-positive tumors that have innate or acquired resistant to

trastuzumab is an important clinical problem. Here we report a two-component delivery system for induced internalization of HER2-targeted nanocarriers with therapeutic cargo based on click-chemistry in situ reaction between the pretargeting and therapy carrier components. This pretargeting strategy provides image guidance for therapeutic applications and has been validated in preclinical models of breast cancer.


TRANSLATIONAL IMAGING IN ONCOLOGY (CONTINUED)

10:50 Use of Echocardiography for Safety De-Risking of Oncology Drug CandidatesTerri A. Swanson, MA, LATg, PMP, Preclinical Ultrasound, Global Science & Technology Worldwide Comparative Medicine, PfizerCardiotoxicity is a common finding in safety studies of oncology drug candidates. Changes in cardiac function are an important endpoint for patients taking these medications. We will discuss the use of high frequency ultrasound echocardiography in the rodent for predicting cardiac safety from oncology candidates and certain classes of compounds. Rodent and large animal echocardiography provides standard clinical endpoints such as ejection fraction, fractional shortening and cardiac output for these studies and can be directly translated to the human clinic.

11:20 Proteomic Imaging of Caveolae to Penetrate Solid TumorsJan E. Schnitzer, M.D., Director, Professor of Cellular & Molecular Biology, PRISM, Proteogenomics Research Institute for Systems MedicineAccess inside solid tumors is poor yet critical for imaging and therapeutic agents to be effective. These agents rely on passive movement across endothelial barriers to reach targets inside tumors. Our “proteomic-imaging” efforts discovered a new pathway and class of delivery targets for active transport into tumors. In vivo imaging reveals caveolae-targeted antibodies, drugs, imaging agents, and nanoparticles being pumped across endothelium to achieve >100-fold more tumor delivery and efficacy.


12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own


IMAGING ADVANCES AND END POINTS IN CANCER RESEARCH

1:30 Chairperson’s Remarks

1:35 Translational Imaging in OncologyDaniel P. Bradley, Ph.D., Head of Biomedical Imaging at Takeda Boston, Takeda Pharmaceuticals International Co.Daniel will present on a number of programs that he has directly worked on, or working on, that have been developed in translational imaging in oncology. Importantly, this talk will highlight important lessons learned about collaboration, timing, perspectives and science with a hope that other groups in the imaging community can leverage this information for future developments. The Biomedical Imaging Group balances its portfolio between the use of conventional imaging biomarkers used in a novel biological and/or pharmacological context to advanced imaging techniques.



6th AnnualJune 10-11, 2015 | Boston, MA

2:05 Non-Invasive and Simultaneous Measurement of Pharmacokinetics and Pharmacodynamics in Preclinical Cancer ModelsWerner Scheuer, Research Leader, Pharma Research and Early Development, Discovery Oncology, Roche Diagnostics GmbHNon-invasive imaging modalities (optical and micro-computed tomography) in combination with ex vivo analysis (3D-multispectral fluorescence microscopy, FACS) are an undispensable tool to assess the anti-tumoral efficacy of new compounds. Proliferation of tumor cells, metastasis, angiogenesis, and induction of apoptosis as well as phosphorylation of kinases can be monitored in mice carrying tumor cells s.c. or orthotopically. The quantification of these pharmacodynamics (Pd) read-outs are combined with optical pharmacokinetics (Pk). The simultaneous measurement of Pd and Pk reduces the number of animals significantly and provides a comprehensive evaluation of new drugs.

2:35 Normalizing Tumor Microvasculature and MicroenvironmentDai Fukumura, M.D., Ph.D., Deputy Director, Edwin L. Steele Laboratory; Biologist, Department of Radiation Oncology, Massachusetts General Hospital; Associate Professor, Harvard Medical SchoolIntravital microscopy techniques and sophisticated animal models have been providing unprecedented molecular, cellular, anatomical and functional insights in tumor biology. Tumor microvasculature is structurally and functionally abnormal hindering drug delivery and inducing a hostile microenvironment that causes ineffectiveness of anti-tumor treatments. Imbalance of pro- and anti-angiogenic factors is causing these pathophysiological features in the tumor. Hence, restoring the balance of these factors in tumors may “normalize” tumor vasculature, improve its function and microenvironment, and enhance the efficacy of cytotoxic therapies.

3:05 Companion Diagnostic Co-Development ModelsSusanta Sarkar, Ph.D., Director, Translational/Clinical Imaging, Sanofi OncologyA number of antibody-drug conjugates (ADC) are currently in clinical trials driven by recent technological progress. However, most ADC targets are not universally expressed on a given tumor type and will require a companion diagnostic to select patients that are likely to benefit from the particular ADC. A non-invasive imaging-based companion diagnostic will allow real time measurement of antigen expression in the tumor, thus enabling patient stratification in real time by identifying patients who are likely to respond to the ADC.





7:00 Close of Day

THURSDAY, JUNE 11


CASE STUDIES8:35 Preclinical Development of Peptide Radiotracers for Detecting Visceral Amyloid Associated with Multiple MyelomaJonathan Wall, Ph.D., Professor of Medicine, Human Immunology and Cancer Program; Director, Amyloid and Preclinical Molecular Imaging Laboratory, University of Tennessee Graduate School of MedicineMultiple myeloma, the second most common hematologic malignancy in the US, and related plasma cell dyscrasias, are characterized by the secretion of monoclonal immunoglobulin light chains that often deposit as insoluble amyloid fibrils in visceral organs. The abundance of amyloid deposits and their anatomic distribution often inform prognosis and treatment options. At present there are no clinical methods for the non-invasive, quantitative measurement of amyloid. To this end we have generated synthetic, poly-basic peptides that preferentially bind amyloid and, when radiolabeled, can be used for disease detection by molecular imaging.

9:05 PARP1 Status Annotation in Cancers of the Oral CavityThomas Reiner, Ph.D., Assistant Member, Memorial Sloan-Kettering Cancer Center; Assistant Attending Chemist, Radiochemistry & Imaging Sciences Service; Assistant Professor, Weill Cornell Medical CollegeThe enzyme PARP1 has attracted attention for its diagnostic and prognostic value, and quantification of PARP1 expression could impact the clinical decision-making process directly. A noninvasive imaging tool that can unambiguously quantify the expression of PARP1 in vivo, however, is an unmet clinical goal. Here, we report on the use of a PARP1 imaging agent as a probe for the early detection of oral cancer, discuss its pharmacological properties and selectivity in vivo, and illustrate its potential impact on future clinical research.

9:45 Utility of 3D Ultrasound and Photoacoustic Imaging in Subject Stratification and Treatment PredictionSrivalleesha Mallidi, Ph.D., Research Fellow, Laboratory of Tayyaba Hasan, Harvard-MITPrediction of response and tumor recurrence following a given therapy is necessary for effective treatment. In this talk, we demonstrate an approach towards this goal with an example of photodynamic therapy (PDT) as the treatment modality and photoacoustic imaging (PAI) as a non-invasive, response and disease recurrence monitor in a murine model of glioblastoma (GBM). PDT is a photochemistry-based, clinically used technique that consumes oxygen to generate cytotoxic species thus causing changes in blood oxygen saturation (StO2).



IMAGE GUIDED INTERVENTIONS 11:30 Drug and Diagnostic Imaging with Mass SpectrometryNathalie Agar, PhD, Assistant Professor of Neurosurgery, Assistant Professor of Radiology, Harvard Medical School, Director, Surgical Molecular Imaging

»12:00 PM KEYNOTE PRESENTATION: CLINICAL TRANSLATION OF NEAR-INFRARED FLUORESCENCE IMAGING FOR IMAGE-GUIDED SURGERY

John V. Frangioni, M.D., Ph.D., Professor, Department of Medicine and Radiology, Harvard Medical SchoolInvisible near-infrared (NIR) light in the 700 nm to 900 nm range penetrates several millimeters into living tissue. In conjunction with target-specific fluorescent contrast agents, NIR light can highlight all desired structures on the surgical field, such as tumors that need to be resected and critical structures that need to be avoided. This talk will introduce the first principles of near-infrared light for surgical guidance and review clinical translation of NIR imaging systems and contrast agents.



Inaugural


Suggested Event Package:June 10-11: New Models for Predicting Drug Toxicity Conference

June 11-12: 3D Cellular Models Conference

June 11 Dinner Short Course*: 3D Printing* Separate registration required.


June 10-11


Imaging in Oncology

June 11-12


3D Cellular Models THURSDAY, JUNE 11


APPLYING 3D MODELS FOR TOXICOLOGY RESEARCH2:00 Chairperson’s Opening Remarks Jeffrey Morgan, Ph.D., Professor, Medical Science and Engineering, Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University

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2:05 FEATURED PRESENTATION: 3D SPHEROIDS FOR INVESTIGATING DRUG UPTAKE, ACCUMULATION AND TRANSPORTJeffrey Morgan, Ph.D., Professor, Medical Science and Engineering, Department of Molecular Pharmacology, Physiology and Biotechnology, Brown UniversityIn addition to recapitulating normal and disease phenotypes, the

small 3D microtissues formed by multi-cellular spheroids also mimic the physical/biological barriers to drug penetration that are significant contributors to a drug’s efficacy as well as toxicity. This talk covers the use of micro-mold technology to form long-lived designer spheroids and their use to quantify drug transport.

2:35 Engineered 3D Microsystems: Recapitulating in vivo Form, Function and ResponsesChristopher S. Chen, M.D., Ph.D., Professor, Biomedical Engineering, Boston University and Wyss Institute for Biologically Inspired Engineering, Harvard UniversityThe 3D organization of cells defines the adhesive, mechanical and soluble microenvironment that ultimately governs cell phenotype. Understanding how forces, form and cellular function are related provides a mechanism for engineering 3D cultures that can more faithfully reproduce in vivo function. This presentation discusses both the underlying fundamental insights and examples of engineered cultures that have the potential for enhancing discovery, validation and safety studies.

3:05 When Time Is the Third Dimension: Combining Computer Simulation and Primary Tissue Cell Culture to Identify Tissue Stem Cell-Toxic Drug CandidatesJames L. Sherley, M.D., Ph.D., Director, Asymmetrex, LLCScreening out drug candidates that are toxic to tissue stem cells before conventional preclinical testing would accelerate drug development and reduce its high cost. Human tissue stem cell toxicity may also elude animal testing and lead to even more expensive failures due to intolerable toxicity in clinical trials or after marketing. AlphaSTEM is a new computer simulation technology for predicting

tissue stem cell toxicity against any human tissue in a relatively inexpensive cell culture format.

TAKING SCREENING INTO A NEW DIMENSION

3:35 NanoCulture Plate (NCP): Scaffold Type Sponsored by High-Throughput 3D Cell Culture SystemM. Mamunur Rahman, Ph.D., PI & Lab Director, 3D Cell Culture, SCIVAX USA, Inc.NCP is engineered with micro-patterned square or honeycomb structure on the plate surface that supports cells to form cell spheroid. NCP is prime for many studies, i.e. signaling, hypoxia, live imaging, anti-cancer drug sensitivity screen, primary cancer cell culture, EMT assay, toxicology or regenerative medicine researches, co-culture, and stem cells differentiation.

3:50 Use of Co-Spheroids Systems for the Sponsored by Analysis of the Impact of Stromal Cells on Anti-Cancer Drug ActivityJan E. Ehlert, Ph.D., Head, Cellular Drug Discovery, ProQinase GmbHIn cancer treatment, stroma-derived microenvironmental cues are suspected to exert an adversary impact on anti-cancer drug efficacy. For taking such influences into account, we established a spheroid-based co-culture system for the analysis of compound effects on the proliferation of tumor as well as of stromal cells. This modular HTS-compatible assay system generates information on stroma-attenuated drug activity that may prove valuable in early drug development to focus on compounds that remain active under microenvironmental conditions.


4:45 Challenges & Opportunities toward Enabling Phenotypic Screening of Complex & 3D Cell ModelsChristophe Antczak, Ph.D., Laboratory Head, CPC Integrated Lead Discovery, Novartis Institutes for Biomedical ResearchMore and more complex and three-dimensional cell models derived from primary or iPS cells are described that recapitulate aspects of in vivo tissue organization and function. Challenges toward enabling high-throughput phenotypic assays relying on these emerging models can be overcome by new opportunities in detection technologies. Progress toward enabling live, minimally invasive readouts is key to being able to take full advantage of more physiologically relevant cell models in drug discovery.

5:15 Developing More Disease-Predictive Assays for Phenotypic ScreeningFabien Vincent, Ph.D., Associate Research Fellow, Assay Development and Pharmacology, Hit Discovery and Lead Profiling, Pfizer Global Research & DevelopmentPhenotypic screening promises to positively impact the translation of preclinical discoveries to the clinic. Nonetheless, not all phenotypic screens will offer the same potential in that regard. A critical question then follows: What are the characteristics of the best phenotypic screens? This presentation covers an analysis of this question conducted by a team of Pfizer scientists as well as proposes three specific criteria to help identify and design the most promising screens.

5:45 3D Skin Equivalents for the Assessment of Skin Health BenefitsTeresa DiColandrea, Ph.D., Senior Scientist, Life Sciences Innovation Core, Procter & GambleThree-dimensional skin and hair equivalents offer the potential for preclinical assessment of technologies for skin health but face challenges in specificity, robustness, scale and cost for integration into screening methods. Examples of characterization and application of 3D models for preclinical studies will be discussed.

6:15 Close of Day

3D Cellular ModelsRevitalizing Phenotypic Screening


3D Cellular ModelsInaugural


FRIDAY, JUNE 12


APPLYING 3D MODELS FOR ONCOLOGY RESEARCH8:35 Chairperson’s RemarksChristophe Antczak, Ph.D., Laboratory Head, CPC Integrated Lead Discovery, Novartis Institutes for Biomedical Research

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8:45 FEATURED PRESENTATION: 3D PRINTING OF IN VITRO CELL/TISSUE MODELS FOR DRUG TESTINGWei Sun, Ph.D., Albert Soffa Chair Professor, Mechanical Engineering, College of Engineering, Drexel University; Professor and Director, Biomanufacturing Research Center, Mechanical Engineering, Tsinghua University Rui Yao, Ph.D., Assistant Professor, Biomanufacturing Research Center, Mechanical Engineering, Tsinghua University This presentation reports on the application of 3D cell printing techniques to construct functional in vitro cell/tissue models for drug testing. Examples of printing of HeLa cells for 3D cervical tumor models in vitro and the printing of micro-organ devices will be presented.

9:15 Engineering the Tumor Microenvironment ex vivo for Translation Studies Using Patient-Derived ExplantsAmir Aref, Ph.D., Instructor, Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical SchoolPersonalized cancer medicine is based on an emerging knowledge of the cancer mutation repertoire and the tailored application of drugs that target altered genes or pathways in individual patients. This work will enhance studies of tumor cell biology in a physiologic context, open a new avenue for drug screening and biomarker development and accelerate the preclinical evaluation of novel personalized medicine strategies for patients in real time.



11:00 Targeting Biomarker Modulation, Cellular Heterogeneity and EMT in a Microfluidic Model for 3D Tumor GrowthImran Rizvi, Ph.D., Instructor, Medicine and Dermatology, Medicine, Brigham and Women’s Hospital and Harvard Medical SchoolUnderstanding the role of hydrodynamic stress as a physical modulator of genetic, molecular and morphologic heterogeneity in tumor metastases may have important implications in treatment resistance and the design of targeted therapies. The impact of flow on tumor morphology and biomarker modulation was investigated in a microfluidic model for 3D ovarian cancer. Flow-induced shear stress caused an increase in epithelial-mesenchymal transition and increased expression and activation of molecular markers associated with aggressive disease.

11:30 Modeling Pain and Peripheral Neuropathy Using Fibroblast-Derived Nociceptor NeuronsElizabeth D. Buttermore, Ph.D., Research Fellow, F.M. Kirby Neurobiology Center, Boston Children’s Hospital; Neurobiology Department, Harvard Medical SchoolCurrent model systems for preclinical pain and peripheral neuropathy studies are not providing adequate options in the clinic. To address this issue, we developed a method for deriving nociceptor neurons in vitro from mouse and human fibroblasts. With these derived neurons, phenotypic screens can be completed to identify novel therapeutic strategies for ailments ranging from chronic pain to chemotherapy-induced neuropathy, with the goal of increased success rates moving into the clinic.

12:00 pm Cancer-on-a-Chip for Target Identification and Drug ScreeningSophie Lelièvre, D.V.M., LLM, Ph.D., Professor, Department of Basic Medical Sciences; Associate Director, Collaborative Science, NCI-Designated Purdue Center for Cancer Research, Purdue University Tissue architecture has been long known as an important feature to reproduce in order to identify pathways that control cancer onset and progression. Here I discuss specifically the impact of tissue geometry, notably that of ductal structures, on the architecture and behavior of breast tumors, and the consequences for the development and assessment of therapeutic approaches.

12:30 Drug Discovery with Patient-Specific 3D Engineered Heart TissuesTetsuro Wakatsuki, CSO, InvivoSciences, Inc.InvivoSciences developed an in vitro disease model that recapitulates individual patient’s cardiomyopathy in 3D engineered heart tissues (EHTs) using the patient-derived cells. Automated cell culture and cardiomyocyte-differentiation protocol improved the productivity and reproducibility for generating patient-specific disease models for drug and diagnostics development.

12:45 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:30 Session Break

ENGINEERING FUNCTIONAL 3D MODELS FROM ORGANS TO SYSTEMS

2:00 Chairperson’s Remarks (Sponsorship Opportunity Available)

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2:05 FEATURED PRESENTATION: ORGANS-ON-CHIPS: ENGINEERING THE CELLULAR MICROENVIRONMENT TO RECREATE TRUE HUMAN PHYSIOLOGY AND ADVANCE DRUG DISCOVERYGeraldine A. Hamilton, Ph.D., President and CSO, Emulate; former Senior Staff Scientist, Wyss Institute for Biologically Inspired

Engineering, Harvard UniversityOrgans-on-Chips are smart in vitro surrogates of the human body that may accelerate the identification of novel therapeutics, ensure their safety and efficacy, and reduce significant drug development costs. We review our Organs-on-Chips platform, which goes beyond conventional 3D cell culture models by recapitulating tissue-tissue interfaces, spatiotemporal chemical gradients, mechanical microenvironments and physiological function in an organ-specific context. Based on experimental data collected from this platform, it is evident that it stands as a more predictive, human-relevant alternative to traditional drug development methods.

2:35 Lab-on-a-Chip Technologies for Automated High-Throughput Drug DiscoveryJeffrey Borenstein, Ph.D., Laboratory Technical Staff, Biomedical Microsystems, Draper LaboratoryWe have developed a range of technologies capable of automating the screening of compounds in a medium- to high-throughput manner. These technologies have been applied to important problems in cardiovascular diseases, in addition to kidney, liver and lung models. In this presentation we demonstrate the use of these prototype lab-on-a-chip systems in several applications.

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3:05 KEYNOTE PRESENTATION: INTEGRATING MULTIPLE ORGANS-ON-CHIPS: WHAT MIGHT WE LEARN, WHAT DO WE NEED AND HOW MIGHT WE DO IT?John P. Wikswo, Ph.D., Founding Director, Vanderbilt Institute for Integrative Biosystems Research and Education and Gordon A. Cain University Professor, Vanderbilt University

Organs-on-chips (OoCs) are beginning to recapitulate human physiology in compact, two- and three-dimensional tissue models that are more accurate than monolayer monocultures on plastic or matrix, and minimize the dilution of paracrine signals intrinsic to Petri-dish or well-plate culture. Refined OoC microfluidics and analytics are now enabling the study of organ-organ interactions, including physiological regulation and drug toxicity. The next step is to optimize insertion of coupled OoCs into the drug development pipeline.



Targeting GPCRsInaugural


Suggested Event Package:June 9 Short Course*: Allosteric Modulators of GPCRs, (PAMs NAMs)

June 9 Dinner Short Course*: Biased GPCR Ligands: Towards Novel Drug Discovery

June 10-11: Targeting GPCRs Conference

June 11-12 Training Seminar: Applying Pharmacology to New Drug Discovery* Separate registration required.

WEDNESDAY, JUNE 10


BIASED SIGNALING8:00 Chairperson’s Opening RemarksConrad Cowan, Ph.D., Head, Biology, Trevena

« 8:05 KEYNOTE SPEAKER: SYSTEMS

PHARMACOLOGY LINKS GPCRS WITH RETINAL DEGENERATIVE DISORDERSKrzysztof Palczewski, Ph.D., Professor and Chair, Department of Pharmacology, School of Medicine, Case Western Reserve UniversityA systems pharmacology approach employs signaling pathways to

enhance rational therapeutic strategies for treating complex disorders/diseases. Our proposal for systems pharmacology starts with a quantitative transcriptome analysis not only of cells, but also of tissues and organs of interest. Next, a reliable animal model that recapitulates the human condition(s) must be available to investigate combinations of drugs that act on one or several network pathways to select those most suited for human trials.

8:35 Novel Strategies for Biasing GPCR SignalingJeffrey L. Benovic, Ph.D., Professor and Chair, Department of Biochemistry and Molecular Biology, Thomas Jefferson UniversityG protein-coupled receptors (GPCRs) interact with three families of proteins in a ligand-dependent manner: heterotrimeric G proteins, GPCR kinases and arrestins. These interactions play an essential role in regulating GPCR signaling, trafficking and degradation. In this presentation, I will highlight recent strategies used to bias GPCR signaling with an emphasis on the use of lipidated GPCR peptides (pepducins) to promote GPCR interaction with selective downstream targets.

9:05 Translating Bias: from the Bench to the ClinicConrad Cowan, Ph.D., Head of Biology, TrevenaBiased ligands targeting GPCRs can selectively stimulate or inhibit distinct downstream signaling pathways, and may provide improved therapeutic efficacy and/or reduced side effects relative to unbiased ligands. Preclinical and clinical data will be presented on two of our most advanced biased ligand programs, one a β-arrestin-biased ligand of the Angiotensin type II type 1 receptor for acute heart failure and the other a G protein-biased ligand of the μ-opioid receptor for pain.

9:35 Biased Agonists for Dopamine D2 Receptors: Novel Antipsychotic Drugs?John A. Allen, Ph.D., Principal Scientist, Neuroscience, PfizerWe have generated biased ligands for various Dopamine receptors to test

if selectively engaging signaling pathways will provide new therapeutics for neurological diseases. Using the Dopamine D2 receptor as example, I will describe our effort generating agonists that exclusively activate D2-Gi/o or D2-Beta-arrestin signaling. Agonists that enabled arrestin engagement, but not Gi/o activation, induced prolonged ERK signaling and showed robust antipsychotic activity with reduced motoric side-effects in rodent models.


SELECTIVE SIGNALING10:50 Ligand Bias in the Interaction of Muscarinic M3 Receptor with a Regulator of G Protein Signaling (RGS) Complex, Gβ5-RGS7Vladlen Z. Slepak, Ph.D., Professor, Molecular and Cellular Pharmacology, University of MiamiThe G protein β subunit Gβ5 forms obligatory heterodimers with R7 family RGS proteins. Gβ5-RGS7 can directly bind to M3R and has a dual effect: attenuates the Ca2+ release from stores, while augmenting Ca2+ influx across the plasma membrane. M3R-induced insulin secretion was practically eliminated by Gβ5 knockout, consistent with the idea that Gβ5-RGS7 is necessary for Ca2+ influx in beta cells. Responses to oxotremorine-M were insensitive to Gβ5-RGS7 while pilocarpine-induced signals were particularly strongly inhibited.

11:20 Polypharmacology and Multi-Targeted Directed Ligands (MTDL) for GPCRsRonan Bureau, Ph.D., Professor, Molecular Modelling, CERMN, University of Caen, FranceThe design of new type of ligands (MTDL) able to modulate several biological pathways involved in a specific disease represent a particular challenge. The presentation will concern our last results for alzheimer disease implying 5-HT4 and H3 receptors.

11:50 Structure-Based Computational Approaches for

Sponsored bythe Identification and Optimization of

GPCR Ligands Thijs Beuming, Ph.D., Research Leader, Applications Science, SchrödingerWe present computational strategies for GPCR lead identification and optimization, covering a broad range of applicability. First, we developed a customizable modeling protocol to optimize homology models, as well as a probabilistic model to boost virtual screening enrichment by considering explicit water molecules in the GPCR binding site. For optimizing potency, we validated and applied all-atom MD-based free energy calculations (FEP) to a variety of GPCR targets. Advanced hydration site analysis (WaterMap) was used to explain an unintuitive SAR within a series of triazolylpurine analogues.



ANTIBODIES FOR GPCRs1:30 Chairperson’s RemarksJeffrey L. Benovic, Ph.D., Professor and Chair, Department of Biochemistry and Molecular Biology, Thomas Jefferson University

1:35 Targeting GPCRs with Monoclonal AntibodiesTrevor Wilkinson, Ph.D., Associate Director, Protein Sciences, Antibody Discovery and Protein Engineering, MedImmuneG-protein coupled receptors represent a challenging target class for the isolation

Antibody and Small Molecule Approaches for New Drug Leads


Targeting GPCRsInaugural


and optimization of therapeutic biologics. We have used a combination of immunization and phage display to isolate functional antagonistic antibodies targeting a chemokine receptor and a formyl-peptide receptor which will be presented as case studies. We also describe how combinatorial mutagenesis approaches have been used to make significant improvements to both affinity and species cross-reactivity of a lead molecule and demonstrate that the optimised antibodies show significantly increased potency in cellular disease assays.

2:05 Using StaR Proteins as Antigens to Generate Antibodies to GPCRsAli Jazayeri, Ph.D., Head, Engineering, HeptaresGPCRs represent excellent antibody targets given their central role in the pathology of many diseases and cell surface location. However GPCRs make poor antigens due to their conformational flexibility, low expression levels, inherent instability and hydrophobic nature. Using protein engineering approaches we create conformationally stabilised receptors (StaRs) that can be purified to high purity and homogeneity with enhanced half-life. StaRs allow generation of high quality antigens that can be used to raise functional antibodies.

2:35 Nanobodies as Tools for Probing GPCR Structure and FunctionAndrew C. Kruse, Ph.D., Assistant Professor, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolHeavy-chain only camelid antibodies (nanobodies) have emerged as powerful and versatile tools in GPCR structural biology. Their use has enabled important insights into the structural basis for GPCR activation and allosteric regulation by small molecule ligands, including active-state structures of adrenergic and muscarinic receptors. I will discuss the methods used for identifying conformationally selective nanobodies, and the insights they have offered into the molecular details of GPCR activation and allostery.

3:05 Modulating GPCR Signaling using Conformationally Selective NanobodiesDean Staus, Ph.D., Robert J. Lefkowitz Lab, Postdoctoral Fellow, Department of Medicine, Duke University Medical Center, Howard Hughes Medical InstituteThe signaling cascades induced by ligand binding to a GPCR are mediated by stabilization of specific receptor conformations which leads to the coupling and activation of G-protein and β-arrestin. A total of 18 conformationally selective single domain Camelid antibodies (nanobodies) were tested for their ability to modulate beta-2-adrenergic receptor dependent signaling. When expressed intracellularly (intrabodies), these nanobodies inhibited G protein activation, G protein–coupled receptor kinase (GRK)–mediated receptor phosphorylation, β-arrestin recruitment, and receptor internalization to varying extents.





7:00 Close of Day

THURSDAY, JUNE 11


BIOSENSORS AND LABEL-FREE ADVANCES8:35 Chairperson’s RemarksNeil Burford, Ph.D., Senior Research Investigator II, Leads Discovery and Optimization, Bristol- Myers Squibb

8:45 Development and Validation of Biosensors for GPCRsXavier Leroy, Ph.D., Project Leader and Promoter, Associate Director, Drug Discovery, Actelion Pharmaceuticals

9:15 Cell-Based Label-Free Dynamic Mass Redistribution Assays for Elucidating GPCR-Mediated SignalingStephanie Hennen, Ph.D., Senior Scientist, Department of Incretin Biology, Global Research Organization, Novo Nordisk A/SThe majority of techniques currently employed to examine signaling behavior of GPCRs requires artificial labels. In contrast to these classical methods, a number of novel label-free technologies have emerged recently that are competent to resolve receptor activity as integrated cellular response. The present talk will introduce a label-free method based on dynamic mass redistribution and attempt to show the strengths of holistic label-free detection as compared with classical functional assays but also highlight the challenges.

9:45 Putting a STOP: Structural Visualization of GPCR DesensitizationArun Shukla, Ph.D., Professor, Department of Biological Sciences and Bioengineering, Indian Institute of Technology and Wellcome Trust/DBT Indian Alliance Intermediate FellowThe functions of G-protein coupled receptors (GPCRs) are primarily mediated and modulated by the heterotrimeric G proteins, the G-protein coupled receptor kinases (GRKs), and the β-arrestins. Binding of β-arrestins hinders G protein coupling and leads to receptor desensitization. I will discuss our efforts to understand the structural basis of GPCR-β-arrestin interaction and how this interaction mediates desensitization of GPCRs.

10:15 A Label-Free, Solution-Based Affinity Assay Sponsored by for Allosteric GPCR Ligand Binding Using Back-Scattering InterferometryRichard J. Isaacs, Ph.D., Applied Research Supervisor, Molecular Sensing, IncIntegral membrane proteins such as GPCRs are critical targets for drug discovery but present a host of challenges to the characterization of their binding affinity for small molecules. Determination of allosteric binding in GPCR targets is especially valuable and extremely challenging information to obtain by established binding assay platforms, but can be addressed through a label-free solution-based direct-binding technology, back-scattering interferometry (BSI).


ALLOSTERIC MODULATORS11:30 Positive Allosteric Modulators of Opioid ReceptorsNeil Burford, Ph.D., Senior Research Investigator II, Leads Discovery and Optimization, Bristol-Myers SquibbOpioid receptors are among the most studied GPCRs and are the targets for opiate ligands including morphine, which are key drugs used in the management of pain. However, these opiate ligands also exhibit serious receptor-mediated side effects including tolerance and dependence. The recent discovery of opioid receptor positive allosteric modulators by our lab offers a novel approach for future pain medications because of the potential advantages allosteric ligands have over orthosteric ligands.

12:00 pm mGluR3 PAM as a GDNF-inducer Strategy for the Treatment of Neurodegenerative DisordersStephan Schann, Ph.D., Head of Research, Domain TherapeuticsGlial cell line-derived neurotrophic factor (GDNF) is a peptide that previously showed clinical efficacy for the treatment of Parkinson’s disease. mGluR3 constitutes a novel target that could lead to neuroprotection through production of GDNF. This potential was demonstrated with an orthosteric mGluR2/3 agonist and KO mice. Novel small molecules mGluR3 PAMs were recently discovered at Domain. These molecules were characterized in neuroprotection and GDNF production models. Our results show that mGluR3 PAMs shared similar activities with the mGluR3 orthosteric agonist.



Inaugural


Suggested Event Package:June 10-11: Chemical Biology for Target Validation Conference

June 11-12: Targeting Histone Acetylation Conference

June 11 Dinner Short Course*: Optimizing Physical Properties of Molecules to Achieve High-Quality Clinical Candidates* Separate registration required.

THURSDAY, JUNE 11


PROBING HDAC INHIBITION2:00 Chairperson’s Opening Remarks

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2:05 KEYNOTE PRESENTATION: ISOFORM SELECTIVE HISTONE DEACETYLASE INHIBITORS (HDACi) IN MULTIPLE MYELOMA (MM)Kenneth C. Anderson, M.D., Director, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Kraft Family Professor of Medicine, Harvard Medical School We have explored the role of broad acting and selective HDACi in

MM preclinically and in clinical trials, both alone and in combination with novel agents. Broad acting HDACi vorinostat and panobinostat or HDAC 6 selective HDACi ricolinostat have been combined with bortezomib to block aggresomal and proteasomal protein degradation, respectively. Ricolinostat combined with immunomodulatory drugs lenalidomide or pomalidomide downregulate cMyc. We will update the rationale and use of isoform selective HDACi to both increase response and improve tolerability in MM.

2:35 A Benzoylhydrazide Class of HDAC Inhibitors that Selectively Inhibit Class I HDACs Daiqing Liao, Ph.D., Associate Professor, Department of Anatomy and Cell Biology, College of Medicine, University of FloridaClass I HDACs are therapeutic targets, and inhibitors specific to these HDACs hold a considerable therapeutic promise for treating cancer and other diseases, but toxicity and poor drug properties of known class I HDAC inhibitors may hamper their clinical applications. This presentation will discuss a novel benzoylhydrazide class of class I HDAC-selective inhibitors, which display unique mechanisms of HDAC inhibition and anti-proliferative effects.

3:05 Chemogenomic Approaches to Spatiotemporal Regulation of HDAC ActivityRalph Mazitschek, Ph.D., Assistant Professor, Center for Systems Biology, Chemical Biology Platform, Massachusetts General HospitalHDACs are master regulators of chromatin structure and function. Beyond modulating histones acetylation they are recognized as regulators of non-histone proteins. HDAC inhibitors have been used as tool compounds to study basic biology and recognized as promising therapeutics. However, systemic exposure is often not well tolerated, or does not provide the required resolution in biological model systems. To address these shortcomings we have developed a new approach to control HDAC activity with greater spatial and temporal resolution.



4:45 Novel Approaches to the Discovery of Isoform Selective HDAC InhibitorsFlorence Wagner, Ph.D., Senior Group Leader, Medicinal Chemistry, Stanley Center for Psychiatric Research, The Broad Institute of MIT and HarvardWhile a number of HDAC inhibitors were discovered over the years, the development of highly potent and isoform selective HDACi is critical not only to refine our understanding regarding the relevant isoform(s) for on-target efficacy but also to mitigate potential mechanism-based, dose-limiting side effects. I will present design strategies that our group has employed towards the discovery of novel HDACi with tuned kinetic (residence time) and thermodynamic binding properties for HDACs 1, 2 and 3.

5:15 In Search of Structurally and Mechanistically Novel Deacteylase ProbesAngela Koehler, Ph.D., Professor, Department of Biological Engineering, MIT and Koch Institute for Integrative Cancer Research, MIT and Associate Member, Broad Institute HDACs regulate numerous biological processes and have been implicated in various diseases, including cancers, psychiatric disorders, metabolic disorders, and inflammatory diseases. Despite significant efforts, many of the biological functions, precise molecular functions, substrates, and binding partners of HDACs are unknown or poorly understood. Selective chemical probes can aid in studying their relevant functions. Toward this end, our lab has employed unbiased binding assays in an effort to uncover molecules with novel patterns of selectivity or chemical structure.

5:45 Imaging HDAC Density and Drug Inhibition in the Human BrainJacob Hooker, Ph.D., Associate Professor, Radiology, Harvard Medical School and Director of Radiochemistry, Martinos Center for Biomedical Imaging, Massachusetts General HospitalInhibition of HDACs is being pursued as a therapeutic strategy and yet we do not know for most diseases the relationship between HDAC density or function and disease progression. We have developed an imaging agent, [11C]Martinostat, to quantify HDAC isoforms non-invasively in humans and are using quantitative imaging to determine the relationships between HDAC and disease in the brain and in peripheral organ systems.

6:15 Close of Day

FRIDAY, JUNE 12


TARGETING SYNERGISTIC PATHWAYS8:35 Chairperson’s RemarksWayne W. Hancock, M.D., Ph.D., Professor of Pathology and Chief of Transplant Immunology, Children’s Hospital of Philadelphia and University of Pennsylvania

8:45 Novel Systems Therapeutics Approach to Efficiently Modulate Histone AcetylationJulen Oyarzabal, Ph.D., Director, Translational Sciences, Center for Applied Medical Research (CIMA), University of Navarra, Spain

Targeting Histone AcetylationInnovative Approaches to Modulate HDACs, HATs and Other Epigenetic Targets


Targeting Histone AcetylationInaugural


We have proposed and validated a systems therapeutics approach, based on a novel mode of action simultaneously targeting two independent but synergistic pathways: phosphodiesterases (PDEs) and HDACs, that significantly induce histone acetylation. Thus, potent HDAC inhibitors are not required to achieve a remarkable level of histone acetylation; minimizing any potential toxicity related to HDAC inhibition. To validate this novel approach an in vitro and in vivo proof-of-concept, focused on Alzheimer´s Disease, using two known pharmacological compounds, as well as novel first-in-class dual inhibitors, will be presented.

9:15 Immunomodulation and HDAC Inhibitors in Breast CancerPamela Munster, M.D., Professor, Medicine, Program Leader Development Therapeutics; Director, Early Phase Clinical Trials’ Program, Helen Diller Cancer Center, University of California, San FranciscoIn previous trials we have shown that HDAC inhibitors modulate estrogen receptor signaling and reverse hormone therapy resistance. One of the steps of acquired hormone therapy resistance is believed to involve upregulation of immune pathways and PD-1 and PD-L1 expression. Several groups have shown a differential regulation of cytotoxic and regulatory T-cells by HDAC inhibitors. We are exploring the role of epigenetic priming to immunotherapy and the differential effects of HDAC inhibitors on T-cells in ER+ breast cancer models and a Phase II clinical trial.

9:45 Selective HDAC Inhibitors in Neurodegenerative DisordersElizabeth Thomas, Ph.D., Associate Professor, Department of Molecular and Cellular Neuroscience, The Scripps Research InstituteHDACs have been recognized as potentially useful therapeutic targets for a broad range of neurological disorders. Our findings demonstrate that inhibition of HDAC1 and HDAC3 isotypes can relieve disease phenotypes in Huntington’s disease model systems. Further studies in our lab have focused on identifying gene targets of selective HDAC inhibitors. Overall, the knowledge of gene targets of HDAC inhibitors should help advance these compounds into clinical practice for neurodegenerative disorders.


UNRAVELING HAT & SIRTUIN BIOLOGY11:00 CBP/p300/PCAF/GCN5 vs. Tip60/Myst1 in Foxp3+ Treg Biology and Anti-Tumor ImmunityWayne W. Hancock, M.D., Ph.D., Professor of Pathology and Chief of Transplant Immunology, Children’s Hospital of Philadelphia and University of PennsylvaniaOur work aims to identify post-translational modifications regulating Foxp3 and thereby the development and/or function of Foxp3+ T-regulatory (Treg) cells. Using genetic and pharmacologic approaches, we show that targeting of CBP or p300, and GCN5 or PCAF, diminishes Foxp3 acetylation and Treg suppressive function and promotes anti-tumor immunity, whereas Tip60 targeting induces lethal autoimmunity. Our data provide new insights into the roles of HATs in Tregs, and how these may be targeted for cancer immunotherapy.

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11:30 KEYNOTE PRESENTATION: CHEMICAL APPROACHES TO UNDERSTANDING HISTONE ACETYLTRANSFERASESPhilip Cole, M.D., Ph.D., Professor and Director, Department of Pharmacology and Molecular Sciences, Johns Hopkins University Medical School

Lysine acetylation/acylation modifications, first identified on histones, are widespread post-translational modifications (PTMs) on cellular proteins and regulate cell growth and gene expression in normal and disease states. This presentation will discuss chemical methods to interrogate HATs, enzymes responsible for catalyzing protein lysine acetylation, and describe progress toward developing HAT inhibitors as therapeutics. We will also describe novel chemical strategies for developing site-specifically modified acyl-Lys containing proteins to explore the role of particular PTMs in regulating protein function.

12:30 pm Sponsored Presentation (Opportunity Available)


1:30 Session Break

UNRAVELING HAT & SIRTUIN BIOLOGY (cont’d)2:00 Chairperson’s RemarksPhilip Cole, M.D., Ph.D., Professor and Director, Department of Pharmacology and Molecular Sciences, Johns Hopkins University Medical School

2:05 Bioorthogonal Probes to Interrogate Functions of Histone AcetyltransferasesY. George Zheng, Ph.D., Associate Professor, Department of Pharmaceutical and Biomedical Sciences, University of GeorgiaElucidating biological and pathological functions of protein lysine acetyltransferases (KATs) greatly depends on the knowledge of the dynamic and spatial localization of their enzymatic targets in the cellular proteome. We report the design and application of bioorthogonal chemical probes for facile labeling and detection of substrates of the major human KAT enzymes. This study provides powerful molecular tools for labeling and mapping KAT targets in the context of complex biological mixtures at the proteomic level.

2:35 New Insights into Protein Acetylation from ChemoproteomicsJordan Meier, Ph.D., Investigator, Chemical Biology Laboratory, and Head, Chemical Genomics Section, National Cancer InstituteA paradox of modern acetylation biology is that while the number of sites of acetylation has climbed rapidly, the number of enzymes thought to catalyze this process has stayed relatively constant. Here we describe the utility of chemical proteomic methods to discover and characterize mechanisms of acetylation in endogenous cellular contexts. Our studies highlight an expanded landscape of lysine acetyltransferases, as well as new strategies to investigate the metabolic regulation and small molecule inhibition of protein acetylation.

3:05 Sirtuin Inhibitors as Anti-Cancer AgentsHening Lin, Ph.D., Professor, Department of Chemistry and Chemical Biology, Cornell UniversitySirtuins are known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases. We have discovered several novel enzymatic activities, such as desuccinylation and defatty-acylation, for several sirtuins with no robust deacetylase activity. This has led to the identification of unknown protein post-translational modifications and revealed new biology. It has enabled us to develop compounds that can inhibit particular sirtuins selectively. Some of the selective sirtuins inhibitors can kill cancer cells in cell culture and inhibit tumor formation in mouse models.



8th Annual


Suggested Event Package:June 9 Short Course*: Drug Metabolism and Its Impact on Decisions in Drug Discovery & Development

June 9 Dinner Short Course*: Navigating the CiPA Landscape

June 10-11: New Models for Predicting Drug Toxicity Conference

June 11-12: 3D Cellular Models Conference

June 11 Dinner Short Course*: How to Best Utilize Organotypic 3D Cell Cultures in Oncology


WEDNESDAY, JUNE 10


HOW USEFUL ARE CURRENT IN VITRO AND IN VIVO MODELS

8:00 Chairperson’s Opening RemarksGary Peltz, M.D., Ph.D., Professor of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine

8:05 Current Use of Stem Cell-Derived Cardiomyocytes to Assess QT Prolongation and ProarrhythmiaBernard Fermini, Ph.D., Associate Research Fellow, Global Safety Pharmacology, Pfizer Global Research & DevelopmentAn increasing number of published studies support the use of human embryonic and iPSC derived cardiomyocytes for the assessment of drug-induced QT prolongation. While some of the studies conclude that these cells represent a suitable predictive model, others question their value based on reports of mixed phenotype, unforeseen pharmacology, and conflicting ion channel profile. In this presentation we review some of the more controversial issues and attempt to provide a holistic view of the field.

8:35 How Useful Are In vitro Tools to Predict Hyperbilirubinemia: Utility of UGT1A1, OATP1B1, OATP1B3, MRP2 and BSEP Inhibition AssaysJae Chang, Ph.D., Senior Scientist, DMPK, Genentech, Inc.Hyperbilirubinemia may arise due to inadequate clearance of bilirubin from the body, a multifaceted process consisting of uptake of bilirubin into hepatocytes facilitated by OATP1B1 and OATP1B3. Once in the hepatocytes, it is extensively glucuronidated by UGT1A1. This talk would 1) provide justification on the potential role of drug transporters in hyperbilirubinemia, 2) show inhibition data against UGT1A1, OATP1B1, OATP1B3, MRP2 and BSEP with marketed drugs and 3) discuss the application of in vitro assays for prediction of hyperbilirubinemia.

9:05 Proteomic Approaches to the Discovery of Preclinical Biomarkers of ToxicityLi-Rong Yu, Ph.D., Associate Co-Director, Biomarkers and Alternative Models Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug AdministrationAdvances of proteomics and its application to toxicological studies have led to the development of a new discipline, toxicoproteomics. One of the major research areas of toxicoproteomics is to identify novel biomarkers of toxicity. Mass spectrometry-based quantitative proteomic approaches have been applied to the identification of biomarkers of multiple organ toxicity in preclinical models.

9:35 Predictivity of in vitro Models Including Co-Cultures for the Detection of Hepatotoxic Drugs in HumansFranck Atienzar, Ph.D., Associate Director, In Silico, In Vitro Toxicology, Non Clinical Development, UCB BioPharma SPRLDrug Induced Liver Injury (DILI) is a major cause of attrition during early and late stage drug development. Consequently, there is a need to develop better in vitro tools for predicting hepatotoxicity in humans. The presentation will focus on the predictivity of different human in vitro models such as primary hepatocytes, HepG2 and co-culture models. Toxicity and metabolism data will be presented to better judge the relevance of such in vitro models.


HOW USEFUL ARE CURRENT IN VITRO AND IN VIVO MODELS (cont’d)

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10:50 KEYNOTE PRESENTATION: MICE WITH ‘HUMANIZED’ LIVERS: FROM SAFER DRUGS TO LIVER REGENERATIONGary Peltz, M.D., Ph.D., Professor of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of MedicineDrug-induced liver injury (DILI) has become a leading cause of acute liver failure, and for regulatory actions after drug approval.

Drugs that produced minimal toxicity in animals sometimes caused significant DILI in humans. The fatalities occurring in 7 of 15 patients treated with fialuridine provides a tragic example of this. We have developed chimeric TK-NOG mice, where transplanted human liver cells replace mouse liver. We recently demonstrated that DILI caused by fialuridine and bosentan were easily detected in chimeric TK-NOG mice, which indicates that their use in preclinical studies could improve drug safety.


12:20 pm Luncheon Presentation to be Announced Heribert Bohlen, M.D., Ph.D., CEO, Axiogenesis AG

Sponsored by


EXPLORING ENGINEERED MODELS1:30 Chairperson’s RemarksMichael Shuler, Ph.D., Samuel B. Eckert Professor of Chemical Engineering and James and Marsha McCormick Chair of Biomedical Engineering, Cornell University

1:35 Body-on-a-Chip Devices for Drug Testing: Opportunities and LimitationsMichael Shuler, Ph.D., Samuel B. Eckert Professor of Chemical Engineering and James and Marsha McCormick Chair of Biomedical Engineering, Cornell UniversityHuman surrogates for drug testing can be created using tissue engineered constructs, microfabrication, and PBPK (Physiologically Based Pharmacokinetic) models and may be used to make better decisions about which drugs to select for human clinical trials. We will describe our “pumpless” system, results with multi-organ models, and progress toward a 10+ organ human model. We will discuss the limitations of such technologies and potential solutions.

2:05 Tissue Chips for Drug Discovery and ScreeningKristin Fabre, Ph.D., Scientific Program Manager, Tissue Chip for Drug Screening Program, National Center for Advancing Translational Sciences (NCATS), NIHThe Tissue Chip Program is supporting development of platforms to mimic human physiology that will recapitulate the complex environment for human multi-cellular

New Models for Predicting Drug Toxicity Effective Use of 3D Cells, Stem Cells, Organotypic Cultures and Humanized Animal Models


New Models for Predicting Drug Toxicity 8th Annual


tissues to be studied. Within five years, major organs systems will be developed and applied to the assessment of biomarkers, bioavailability, efficacy, and toxicity of therapeutic agents prior to clinical trials. It will deliver a valid alternative to standard methodologies and will produce human-physiologically relevant findings, reduce animal experimentation, and improve translational research efficacy.

2:35 Human Contractile Engineered Muscle for Drug and Toxicity StudiesNenad Bursac, Ph.D., Rooney Family Associate Professor, Department of Biomedical Engineering, Duke UniversityCurrent in vitro models of human muscle do not exhibit contractile behavior. We engineered electrically and chemically responsive, contractile human muscle tissues (“myobundles”) made of primary myogenic cells. These biomimetic constructs exhibit aligned architecture, multinucleated and striated myofibers, and a satellite cell pool, and respond to electrical stimuli with twitch and tetanic contractions. Use of GCaMP6-reported calcium responses enables long-term non-invasive tracking of myobundle function and response to drugs and provides a platform for predictive drug and toxicology screening.

3:05 Towards Organoid Microarrays for Screening Within Neural TissuesKrishanu Saha, Ph.D., Assistant Professor, Biomedical Engineering and Bioethics, University of Wisconsin, MadisonCurrent human pluripotent stem cell-derived neural models consist of 2D disorganized cultures of cell phenotypes representative of only one or a few regions of endogenous tissues. This ignores the vast diversity of cell phenotypes and structured 3D niches that exist in vivo and thereby limits their modeling capacity in regulatory science settings. To overcome these limitations, we used emerging microfabrication methods to generate an array of 3D neural tissues (e.g., organoids) within standard multi-well plates for screening purposes.





7:00 Close of Day

THURSDAY, JUNE 11


PREDICTIVITY OF COMPUTATIONAL TOOLS8:35 Chairperson’s Remarks Yvonne Will, Ph.D., Senior Director, Drug Safety and Head, Science and Technology Strategy, Pfizer R&D

8:45 eTOX: Assembling Animal Study Data from 6000 Reports From 13 Pharmaceutical CompaniesPhilippe Marc, Ph.D., Global Head, Informatics, Preclinical Safety, Novartis Institutes for BioMedical ResearchIn 2010, within the Innovative Medicines Initiative, the eTOX project started to extract data from legacy preclinical toxicology reports with the objective of creating a collaborative preclinical study database. The current version of the database contains data for 1791 small molecule drugs and drug candidates extracted from 6105 reports donated by 13 pharmaceutical companies. The database is currently growing by approximately 180 studies per month, and we envisage the creation of the largest preclinical database available.

9:15 Enhanced Prediction of Drug-Induced Liver Injury by the Development of Liver Toxicity Knowledge BaseMinjun Chen, Ph.D., Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug AdministrationHere, we will introduce our efforts to develop the Liver Toxicity Knowledge Base (LTKB), which focuses on collecting drug properties data and aims to develop predictive models for assessing DILI risk in humans. We will discuss some simple rules derived from drug physiochemical and toxicological properties and its significant association with DILI risk in humans. After confirmation and validation, these DILI predictive rules may support decision-making in drug development or regulatory processes to reduce potential DILI liability.

9:45 An In silico Approach to Predict Intrinsic In vitro Cytotoxicity for Compounds in Primary Human HepatocytesBinQing Wei, Ph.D., Scientist, Discovery Chemistry, Genentech, Inc.We present work in progress in the development of a computational model that is used to predict the outcome of hepatocyte screening for a set of preclinical compounds with significant accuracy. We show that this model proved very useful in reducing compound attrition for internal projects. Furthermore, the physicochemical property space that this work has implicated as being associated with toxicity may also provide clues toward understanding the underlying mechanism(s) of toxicity.



NEW PARADIGMS FOR SAFETY TESTING11:30 Bioinformatic and Cheminformatic Approaches to Assess Cardiac ArrhythmiasSiobhan Malany, Ph.D., Chemical Biology Team Leader, Chemical Genomics Center, Sanford Burnham Medical Research InstituteThe combination of hiPSC-cardiomyocytes and real-time cellular impedance measurements has provided for higher throughput toxicological screening in physiologically-relevant cellular assays. We have monitored dose-dependent changes in beat rhythm of hiPSC-cardiomyocytes induced by pharmaceutical compounds. For compounds that induce atypical beat patterns, we apply bioinformatic approaches, limit cycle analysis and autocorrelation, and present quantitative results to examine irregular beat patterns induced by channel blockers and provide automated solutions to analyze large kinetic datasets for web-based reporting.

12:00 pm Assay Platforms for Toxicity Evaluation in Small Molecules and NanomaterialsRobert Damoiseaux, Ph.D., Scientific Director, Molecular Screening Shared Resource, California Nanosystems Institute, University of California, Los AngelesSmall molecule and nano-toxicity can follow quite different paradigms, requiring thoughtful use of adequate assay platforms for toxicity evaluation. In this talk we will have a look at the differences in paradigms and their corresponding assay platforms. We will give examples for each and also present a novel laser scanning cytometry based platform for the direct quantification of genotoxic potential of a substance via quantification of the DNA damage response by quantifying H2AX phosphorylation.



Inaugural


Suggested Event Package:June 10-11: Chemical Biology for Target Validation Conference

June 11-12: Synergistic Use of Functional Genomics Technologies Conference

June 11 Dinner Short Course*: How to Best Utilize Organotypic 3D Cell Cultures in Oncology* Separate registration required.

THURSDAY, JUNE 11


RNAi & CRISPR SCREENS FOR ONCOLOGY2:00 Chairperson’s Opening RemarksCharles Gersbach, Ph.D., Assistant Professor, Department of Biomedical Engineering, Center for Genomic and Computational Biology, Duke University

2:05 An RNAi Screen Utilizing a 3D Spheroid Model Suggests Destabilizing Tumor Architecture as a Potential Anti-Cancer TherapyGeoffrey Bartholomeusz, Ph.D., Associate Professor and Director, siRNA Core Facility, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer CenterThe compact architecture of solid tumors results in hypoxia that contributes to chemotherapy/radiation resistance. We propose targeting non-neoplastic components within the tumor architecture as an effective alternative anti-cancer therapy. Using a high throughput RNAi screen and a multicellular tumor spheroid model we identified TLR4 as a potential target. Silencing TLR4 inhibited the expression of E-cadherin, altered the integrity of the spheroid architecture, reduced hypoxia, inhibited the hypoxic tolerance response and sensitized MCTS to radiation.

2:35 Modeling Cancer In vivo Using CRISPR/Cas9Sidi Chen, Ph.D., Postdoctoral Fellow, Laboratory of Dr. Feng Zhang, Broad Institute and the Department of Brain and Cognitive Sciences, Massachusetts Institute of TechnologyCancer genomics has revealed hundreds to thousands of mutations associated with human cancer. To test the roles of these mutations, we applied CRISPR/Cas9-mediated genome editing platform to engineer specific mutations in oncogenes and tumor suppressor genes. This results in tumorigenesis in several internal organs in mice. Our method expedites modeling of multigenic cancer with virtually any combination of mutations.

3:05 Combining RNAi and Genome Editing: New Avenues for Orthogonal Validation of Functional Genomic ProfilesSamuel Hasson, Ph.D., Principal Investigator, Neuroscience, Pfizer, Inc.RNAi-based functional genomics is a staple of gene pathway and drug target exploration. While great strides have been made in the reagents and workflows for shRNA and siRNA screening, there is a need for tools to provide rapid orthogonal validation of gene candidate that emerge from RNAi campaigns. CRISPR, CRISPRi, and CRISPRa are not only developing into primary screening platforms, they are a promising method to compliment RNAi and enhance the quality of functional genomic datasets.



USING GENE EDITING FOR DRUG DISCOVERY4:45 Manipulating Cell Phenotype with CRISPR/Cas9-Based Epigenome EditingCharles Gersbach, Ph.D., Assistant Professor, Department of Biomedical Engineering, Center for Genomic and Computational Biology, Duke UniversityNew methods for programming cell phenotype have broadly enabled drug screening, disease modeling, and regenerative medicine. However many of the current protocols are slow, inefficient, and lead to heterogeneous cell populations. We are exploring genome engineering tools, such as CRISPR/Cas9-based gene regulation and epigenome editing, to more precisely reprogram gene networks and control cellular decision making. We have successfully used these tools to generate cell sources useful for many areas of biotechnology.

5:15 Use of CRISPR/Cas9 Technology to Study Retinal Development and DiseaseDonald Zack, M.D., Ph.D., Associate Professor of Ophthalmology and Neuroscience, Johns Hopkins University School of MedicineAdvances in human stem cell technology have made possible the differentiation of retinal eyecups in vitro. We have been using CRISPR/Cas9 technology to generate retinal cell type-specific reporter ES and iPS lines and to introduce retinal degeneration-associated mutations. These reporter lines can be used to follow retinal neuronal specification during differentiation, they allow the purification of specific cell types by sorting and immunopanning, and they also are useful for the development of drug screening assays.

5:45 A Versatile Functional Genetics Platform for Malarial Parasites Enabled by Efficient CRISPR-Mediated Genome EditingJacquin C. Niles, M.D., Ph.D., Associate Professor of Biological Engineering, Massachusetts Institute of TechnologyFunctional genetics in the human malaria parasite, Plasmodium falciparum, has previously been frustratingly inefficient and time consuming. This bottleneck has limited the opportunities to validate and prioritize parasite targets to motivate the development of new therapeutics. We have now established strategies for robustly achieving controllable gene expression, and have integrated these into an experimental framework that facilitates efficient interrogation of virtually any target parasite gene using CRISPR/Cas9 editing. With these technologies, we are querying the essentiality of parasite proteins to validate them as potential drug targets and developing approaches to identify the targets of compounds having antimalarial activity.

6:15 Close of Day

Synergistic Use of Functional Genomics TechnologiesExploiting RNAi and Gene Editing For Drug Discovery

WorldPharmaCongress.com World Preclinical Congress | 23


InauguralJune 11-12, 2015 | Boston, MA

FRIDAY, JUNE 12


EXPLORING NEW ASSAYS & PLATFORMS8:35 Chairperson’s RemarksJames Inglese, Ph.D., Head Assay Development & Screening Technologies, National Center for Advancing Translational Sciences (NCATS) and Adjunct Investigator, National Human Genome Institute (NHGRI)

«

8:45 KEYNOTE PRESENTATION: GENOME EDITING-ENABLED HTS ASSAYS FOR CHEMICAL BIOLOGY AND TRANSLATIONAL RESEARCHJames Inglese, Ph.D., Head Assay Development & Screening Technologies, National Center for Advancing Translational Sciences (NCATS) and Adjunct Investigator, National Human Genome Institute (NHGRI)

In Parkinson’s disease (PD) loss of function mutations in the Parkin gene (PARK2) are associated with early-onset forms of PD suggesting a role in neuronal survival. We therefore have developed qHTS assays using novel coincidence reporter technology targeting the PARK2 genetic locus to uncover pathways and pharmacological agents that can modulate transcription of this gene. Findings from the qHTS of several thousand drugs and chemical probes using this novel reporter biocircuit-based assay will be discussed.

9:45 High Content RNAi Screening with Persomics: Sponsored by Reduction of Scale and Cost with Turnkey Printed LibrariesNeil Emans, Ph.D., CEO, Persomics USA, Inc.RNA interference is routinely used in High Content and Phenotypic screening. However, set-up and operational costs of conventional methods remain beyond the scope of individual labs or limit screens in facilities. Persomics technology miniaturizes, accelerates and de-industrializes RNAi screening. Turnkey, preprinted libraries enable off-the-shelf focused screens and integrate with High Content platforms, and existing image analysis strategies. This lowers cost, labor, waste and overall time for any scale of screening; enabling individual labs or facilities to do more.



11:00 Massively Parallel Combinatorial Genetics for Developing Combinatorial TherapeuticsTimothy Lu, M.D., Ph.D., Associate Professor, Synthetic Biology Group, Department of Electrical Engineering and Computer Science and Department of Biological Engineering, Synthetic Biology Center, Massachusetts Institute of TechnologyWe have developed technologies for the scalable and barcoded assembly of high-order combinatorial genetic libraries. These strategies enable multiplexed tracking of individual genetic combinations with next-generation sequencing in pooled screens. We have used these technologies to perform massively parallel high-order combinatorial genetics in bacteria and human cells and to modulate phenotypes relevant to important human diseases. Insights derived from massively parallel combinatorial genetics can inform the design of effective and novel combinatorial therapeutics.

11:30 Building, Using and Maintaining a Functional Genomics ArsenalRobert Damoiseaux, Ph.D., Scientific Director, Molecular Shared Screening Resource, California NanoSystems Institute, University of California, Los AngelesFunctional Genomics is one of the most useful modalities for pre- and post-screen target identification and validation. Functional genomics platforms include cDNA, siRNA, lentiviral shRNA and CRISPR and each platform has unique advantages and constraints. Here, we will discuss these properties, talk about how to organize and build a functional genomics arsenal that contains such a comprehensive set of tools and cover some of the most common issues encountered during maintenance and use of these tools.

12:00 pm Multiplexed Gene Editing of Human Pluripotent Stem CellsKrishanu Saha, Ph.D., Assistant Professor, Biomedical Engineering and Bioethics, University of Wisconsin, MadisonHuman pluripotent stem cells possess unique ability to mature into any cell type of the body, and therefore are attractive platforms for disease modeling, toxicology and regenerative medicine research. We developed multiplexed CRISPR/Cas9 gene editing tools to insert reporters, knockout or correct candidate genes in patient-specific pluripotent stem cells. Our strategies exploit patterned biomaterial substrates with live-imaging to increase throughput and screening for desired phenotypes in edited cell populations.



1:30 Session Break

REFINING THE USE OF CRISPR TECHNOLOGY2:00 Chairperson’s Remarks (Sponsorship Opportunity Available)

2:05 CRISPR Tools for Gene Regulation ApplicationsLei Stanley Qi, Ph.D., Assistant Professor, Department of Bioengineering, and Department of Chemical and Systems Biology, Stanford UniversityPrecise regulation of genes for activation or repression is an important approach for cell engineering and disease modeling. We develop the bacterial CRISPR system as a toolset for sequence-specific gene regulation. The CRISPR tools enable multiplexable, inducible and high-throughput activation or repression of mammalian genes, allowing genome wide perturbation for probing gene networks. The CRISPR technology thus provides a powerful screening approach to studying gene function and chemical genomics in addition to the RNAi method.

2:35 Small Molecules Modulating CRISPR EditingSheng Ding, Ph.D., William K. Bowes, Jr. Distinguished Investigator, Gladstone Institute of Cardiovascular Disease; Professor, Department of Pharmaceutical Chemistry, University of California, San FranciscoCRISPR-Cas9 system has emerged as an effective tool for genome editing, but challenges remain. To enhance CRISPR-mediated gene editing, we screened chemical libraries and had identified distinct small molecules that can enhance either HDR-based gene knock-in or NHEJ-based knock-out. The use of small molecules provides a simple and effective strategy that enhances precise genome engineering applications and facilitates the study of DNA repair mechanisms in mammalian cells.

3:05 Application of Genome Editing to Generate Animal Models for Drug DiscoveryMyung Shin, Ph.D., Principal Scientist, Biology-Discovery, Genetics and Pharmacogenomics, Merck Research LaboratoriesRecent advances in genome editing have greatly accelerated and expanded the ability to generate animal models. These tools allow generating mouse models in condensed timeline compared to that of conventional gene-targeting knock-out/knock-in strategies in ES cells. Moreover, genome editing methods have expanded the ability to generate animal models beyond mice. In this talk, we will discuss the application of ZFNs and CRISPRs to generate various animal models for drug discovery programs.



Inaugural

Suggested Event Package:June 9 Short Course*: Imaging of Blood-Brain Barrier Function

June 9 Dinner Short Course*: Understanding and Dealing with Drug Disposition in CNS

June 10-11: Blood-Brain Barrier Conference* Separate registration required.

WEDNESDAY, JUNE 10


THE BLOOD-BRAIN BARRIER AT SITES OF PATHOLOGY

8:00 Chairperson’s Opening RemarksMargareta Hammarlund-Udenaes, Ph.D., Professor, Translational PK/PD, Department of Pharmaceutical Biosciences, Uppsala University

« 8:05 KEYNOTE PRESENTATION: REGULATION

OF THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASERichard Daneman, Ph.D., Assistant Professor, University of California, San FranciscoThe blood-brain barrier (BBB) is crucial to ensure proper neuronal function and protect the CNS from injury and disease. We have

used genomic, genetic and molecular approach to elucidate the cellular and molecular mechanisms that regulate the formation of the BBB as well as the mechanisms that lead to its dysfunction during disease.

8:35 Targeting Vascular Dysfunction to Improve CNS HealthRobert D. Bell, Ph.D., Principal Scientist, Neurovascular Biology Lab Head, Pfizer, Inc.The vascular system plays an integral role in maintaining central nervous system (CNS) health. Both systemic circulatory changes and alterations directly within the BBB have been suggested to contribute to both the onset and progression of several neurological conditions. In addition, emerging evidence suggests that vascular risk factors including hypertension, diabetes, obesity, atherosclerosis, metabolic syndrome, and stroke can negatively impact BBB function. The relationship between systemic vasculature and BBB in health and disease will be reviewed.

9:00 Cancer-Derived Extracellular Vesicles Promote Brain MetastasisTakahiro Ochiya, Ph.D., Chief, Molecular and Cellular Medicine, National Cancer Center, JapanBrain metastasis is an important cause of mortality in breast cancer patients. A key event during brain metastasis is the migration of cancer cells through the blood-brain barrier (BBB), which consists of the endothelium and surrounding cells. Transfer of extracellular vesicles (EVs) derived from the cancer cells represents a novel mechanism of communication between cancer cells and normal cells. Here, we show that breast cancer–derived EVs promote brain metastasis by destruction of BBB.

9:25 Do We Always Need to Cross the Blood-Brain Barrier?Lois A. Lampson, Ph.D., Associate Professor of Neurosurgery, Brigham & Women’s Hospital / Harvard Medical SchoolThe BBB does not always impede therapy for the brain. Migratory cells, including immune effector cells, can enter, and their activity can be modulated before they enter. Some agents work from outside the brain: systemic antibody can prevent entry of drugs or pathogens, or even draw material out of the brain. Differences between the BBB at sites of pathology vs. normal brain can help to concentrate therapy at target sites.

9:50 Understanding Antibody Penetration through Blood-Brain Barrier Using Cell Fractionation and Quantitative ProteomicsArsalan Haqqani, Ph.D., Research Officer, Human Health Therapeutics Portfolio, National Research CouncilBetter understanding of mechanism(s) of antibody penetration through BBB is needed to deliver therapies into the CNS. We describe a multiplexed quantitative method, involving endosome fractionation and label-free targeted mass spectrometry, to track and quantify BBB-crossing antibodies in various intracellular compartments of brain endothelial cells. The results show that the method has a potential to quantitatively compare the trafficking of multiple BBB-crossing antibodies, providing an insight into mechanism and antibody characteristics that favor their BBB transcytosis.


UNDERSTANDING & PREDICTION OF BRAIN PENETRATION: PRECLINICAL MODELS, TOOLS &

UNMET CHALLENGES10:50 Human Pluripotent Stem Cell Modeling of the Blood-Brain BarrierEric V. Shusta, Ph.D., Professor, Chemical and Biological Engineering, University of Wisconsin, MadisonA renewable source of human BBB endothelium could prove enabling for brain research and pharmaceutical development. We demonstrate that endothelial cells generated from human pluripotent stem cells (hPSCs) can be specified to possess many BBB attributes, including well-organized tight junctions, polarized efflux transport, and nutrient transporter expression. Importantly, hPSC-derived BBB endothelial cells also respond to cues provided by other cells of the neurovascular unit such as human pericytes, astrocytes and neurons to generate very tight barrier properties.

11:20 FEATURED PRESENTATION: DELIVERY OF SMALL AND LARGER DRUGS ACROSS THE BBB – TO MEASURE IS TO KNOWMargareta Hammarlund-Udenaes, Ph.D., Professor, Translational PK/PD, Department of Pharmaceutical Biosciences, Uppsala UniversityMethods for measuring delivery of drugs across the BBB are

now available to accommodate the unbound, active moiety, thereby providing important information on success rate of compounds for CNS action. The talk will include discussions on the factors needed to be taken into consideration and methods of choice, as well as new information on regional differences in BBB transport and brain distribution. Quantitative results on nanocarrier delivery will also be discussed.

Blood-Brain BarrierNew Understanding, Strategies and Tools for Delivering Therapy to the Brain



Blood-Brain BarrierInaugural





UNDERSTANDING & PREDICTION OF BRAIN PENETRATION: PRECLINICAL MODELS, TOOLS &

UNMET CHALLENGES1:30 Chairperson’s RemarksRichard Daneman, Ph.D., Assistant Professor, University of California, San Francisco

1:35 MRI-Guided Focused Ultrasound Activated Stem Cell Facilitated Blood-Brain Barrier OpeningKing C. Li, M.D., FRCP(C), MBA, Senior Associate Dean for Clinical and Translational Research, Professor and Chair, Department of Radiology, Wake Forest School of MedicineThe objective of this project is to create a remote-controllable stem cell-based strategy to allow us to open up the blood-brain barrier at the time and place of our choosing. Drugs and therapeutic agents up to at least 300 nm in size can be delivered through the blood-brain barrier using this technology. This novel paradigm utilizing image-guided focused ultrasound and stem cells can potentially be applied to all diseases that affect the central nervous system.

2:05 New Blood-Brain Barrier Shuttles: Phenotypic Screens and Targeted ProteomicsDanica Stanimirovic, Ph.D., Director, Translational Bioscience, Human Health Therapeutics Portfolio, National Research Council of CanadaThe blood-brain barrier (BBB) expresses a myriad of receptors and transporters at its luminal surface, yet only a handful of targets have been used to develop molecular Trojan horses for brain delivery of large molecules. We have identified novel receptor-ligand pairs as brain delivery platforms using workflows that combine `function-first` screening of antibody display libraries and targeted proteomics to understand their trafficking mechanisms across the BBB.

2:35 Paracellular Portal to the CNS: Are Macromolecules Permitted?Pankaj Karande, Ph.D., Assistant Professor, Department of Chemical & Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic InstituteDelivery of macromolecules into the central nervous system (CNS) is a formidable challenge. The paracellular route has long been considered an exclusive pathway for entry of small water soluble molecules and ions but it can serve as an attractive portal for delivery of proteins, polypeptides, and enzymes. We will discuss our recent discovery of short peptide vectors, PEPDARTs, that specifically target the paracellular pathway into the CNS for delivery of macromolecular cargo.

3:05 CNS Uptake of Large Molecules and Peptides: PK Profile and Applications to Drug Discovery & DevelopmentSara Belli, Ph.D., DMPK Project Leader, Pharmaceutical Sciences/p-RED, Roche Innovation Center BaselLarge molecules have great potential as CNS therapeutics since they are able to mimick function of endogenous neuropeptides, reducing expression of disease-related genes or clearing pathological protein aggregates. Developing novel, effective, and safe drugs for CNS diseases is hindered by blood–brain barrier reducing distribution of large molecules candidates to brain. Herein, an overview on current knowledge with examples of brain targeting approaches will be given focusing on PK and PKPD profiling.





7:00 Close of Day

THURSDAY, JUNE 11


DELIVERING THERAPIES ACROSS BBB: CASE STUDIES & UPDATES FROM THE INDUSTRY

8:35 Chairperson’s RemarksLois A. Lampson, Ph.D., Associate Professor of Neurosurgery, Brigham & Women’s Hospital / Harvard Medical School

8:45 BBB Disruption and Drug Delivery in Neurodegenerative DiseaseNga Bien-Ly, Ph.D., Postdoctoral Fellow, Dept. of Neuroscience, Genentech, Inc.It is generally believed that the BBB is disrupted in many neurodegenerative diseases thus suggesting that drug delivery is enhanced as a consequence of BBB leakage. We set out to determine the extent of BBB disruption in mouse models of neurodegeneration, focusing on antibody permeability and Alzheimer’s disease, by assessing the differences in brain uptake of control and transferrin receptor (TfR) bispecific antibodies. These results will aid in determining the necessity of developing improved drug delivery methods for the treatment of neurodegenerative diseases.

9:15 Engineering Lysosomal Enzyme Therapeutics for the Brain as IgG Fusion Proteins that Penetrate the Blood-Brain BarrierRuben Boado, Ph.D., Vice President, Research & Development, ArmaGen Technologies, Inc.BBB-penetration of enzyme therapeutics is enabled by re-engineering recombinant enzyme as IgG fusion proteins, wherein the IgG transport domain targets a specific endogenous receptor-mediated transporter within BBB, such as the human insulin receptor (HIR). The therapeutic domain of the IgG fusion protein exerts the pharmacological effect in brain once across BBB. Several bi-functional IgG-fusion proteins have been engineered using a genetically engineered monoclonal antibody directed to the BBB HIR as the transport domain. First in human trials are planned for 2015.

9:45 FEATURED PRESENTATION: OPEN THE BLOOD BRAIN BARRIER GATE FOR BIOLOGICSPer-Ola Freskgard, Ph.D., Vice Director and Senior Leader, Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd.Although biotherapeutics have vast potential for treating brain

disorders, their use has been limited due to low exposure across the blood-brain barrier (BBB). This talk will describe a Brain Shuttle technology, which can be engineered into a standard therapeutic antibody or other modalities for successful BBB transport. These findings will have major implications for the development of biologics-based treatment of brain disorders.



11:30 Use of a Camelid VHH to Engineer Blood-Brain Barrier Crossing BispecificGraham K. Farrington, Ph.D., Director, Chemical & Molecular Therapeutics, Biological Drug Discovery, Biogen Idec.We have engineered a llama single domain VHH antibody FC5 into mono- and bi-valent proteins fused to a huFc. Upon IV injection in rats up to a 30-fold higher brain exposure was observed compared to control. Upon IV dosing in a Hargreaves model of inflammatory pain up to a 60-fold increase in pharmacological potency was observed. The study demonstrates that modular incorporation of FC5 as the BBB-carrier arm in bi-specific antibodies or antibody-drug conjugates offers an avenue to develop pharmacologically active biotherapeutics for CNS indications.

12:00 pm Blood-Brain Barrier (BBB) Penetrating Dual Specific Binding Proteins for Treating Brain and Neurological DiseasesDenise Karaoglu Hanzatian, Ph.D., Principal Research Scientist, Biologics Discovery, AbbVie Bioresearch Center, AbbVie



MASTERINGMEDICINALCHEMISTRY

Twelfth Annual

Case Studies,Hot Topics &Med ChemStrategy


June 10-11: Mastering Medicinal Chemistry Conference

June 11-12: Property-Based Drug Design in Medicinal Chemistry Conference

June 11 Dinner Short Course*: Optimizing Physical Properties of Molecules to Achieve High-Quality Clinical Candidates* Separate registration required.

WEDNESDAY, JUNE 10


EXECUTIVE PANEL: FUTURE ROLE OF MEDICINAL CHEMISTRY – SCIENCE, TECHNOLOGY & STRATEGY8:00 Chairperson’s Opening RemarksStewart L. Fisher, Ph.D., Principal, SL Fisher Consulting, LLC

8:05 Medicinal Chemistry in the Era of “Big Data”Paul Greenspan, Senior Director, Discovery Chemistry, Takeda BostonThis briefing will focus on the challenges and opportunities that arise from our access to ever-larger quantities of SAR data. How does more data lead to better decision-making? Is our ability to effectively utilize this data keeping pace? What SAR data-mining approaches are having the greatest impact on drug design?

8:12 Target Validation and Reproducibility - A Chemistry PerspectiveMark Bunnage, Ph.D., Vice President, Worldwide Medicinal Chemistry, PfizerReproducibility of the scientific literature is a topic of significant current interest. This discussion will focus on irreproducibility issues in target validation and what it means for medicinal chemistry.

8:19 So You Want to Improve Your Medicinal Chemistry?Jeremy J. Edmunds, Ph.D., Director, Immunology Medicinal Chemistry, AbbvieWhen one considers the considerable expense that is associated with developing a drug, it is clearly the responsibility of the chemist to ensure that they are preparing the most optimal compound. To achieve this we have focused our efforts within Abbvie medicinal chemistry toward excellence in design and excellence in synthesis. Here we will describe the trials and tribulations of this approach.

8:26 Outsourcing of Medicinal ChemistryDavid Bauer, Principal Scientist, Head of Medicinal Chemistry Outsourcing, AmgenThe presentation will give an overview of how leveraging external partnerships is being used at Amgen to support our Medicinal Chemistry organization. The key components of our outsourcing strategy will be discussed.

8:33 Pre-Competitive Collaboration – How AstraZeneca’s Open Innovation Program is Changing the Way We Deliver Medicine to PatientsPamela Hill, Open Innovation Program Manager, Emerging Innovations, AstraZeneca, R&D BostonThe AstraZeneca Open Innovation platform has been created to help us identify and establish mutually beneficial collaborations that will lead to the discovery and development of new medicines. We provide collaborators with access to late-stage compounds, our compound collection as well as our cheminformatics and screening technologies to validate and publish novel science.

8:40 Panel Q&A with Session Speakers

9:05 The Application of Extended Hückel Theory for Sponsored by Pharmacophore ModelingMichael Drummond, Ph.D., Applications Scientist, Chemical Computing GroupPharmacophore models play an essential role in drug discovery. Generating pharmacophore models which encode accurate molecular recognition features are highly dependent on properly defined annotation points. Here we have developed a new approach for pharmacophore modeling which is based on a semi-empirical method using Extended Hückel Theory (EHT). The pharmacophore features generated through the EHT annotation scheme take into account ligand resonance and electron withdrawing effects and are sensitive to non-standard interactions, such as C-H and halogen bond interactions, during pharmacophore screening.

9:35 Small Molecules in Cancer ImmunotherapyJerry L. Adams, Ph. D., Director, Medicinal Chemistry, Immuno-Oncology & Combinations DPU, GlaxoSmithKline Pharmaceuticals

Modulating the immune system through a small molecule approach offers several advantages which are complimentary and potentially synergistic to biologic modalities. Importantly, the successes of checkpoint inhibition provide direction for further advances in the field of immune-oncology, including what roles small molecule drugs might play. This talk will provide an overview of the strategy for and targets druggable by small molecules.


EVOLVING THE KINOME IN DRUG DISCOVERY10:50 Kinase Drug Discovery Past, Present, and FutureMark Bunnage, Ph.D., Vice President, Worldwide Medicinal Chemistry, PfizerOver recent years there has been remarkable progress in the medicinal chemistry design of selective protein kinase inhibitors. There are now over 20 kinase inhibitor drugs on the market and, with the recent approval of the JAK kinase inhibitor Xeljanz® (tofacitinib citrate), we are now seeing kinase drugs emerge for indications beyond Oncology. This presentation will discuss current approaches to kinase inhibitor drug discovery and share a perspective on future directions.

11:20 Secreted Protein Kinases as Novel Regulators of the Extracellular EnvironmentMalcolm Whitman, Ph.D., Professor, Department of Developmental Biology, Harvard School of Dental Medicine; Department of Cell Biology, Harvard Medical SchoolSecreted protein kinases, targeting serine, threonine and tyrosine, have recently been identified and shown to act in the secretory pathway and outside the cell. These novel kinases are divergent from intracellular kinases and represent a new class of drug targets for the modulation of secreted protein and extracellular matrix function.






Mastering Medicinal ChemistryTwelfth Annual


EVOLVING THE KINOME IN DRUG DISCOVERY CONTINUED

1:30 Chairperson’s RemarksRenato Skerlj, Ph.D., Vice President, Drug Discovery and Preclinical Development, Lysosomal Therapeutics, Inc.

1:35 Akt and RNA MetabolismPhilip N. Tsichlis, M.D., Jane F. Desforges Professor of Medicine, Tufts University School of MedicineA phosphoproteomics screen of isogenic cell lines expressing different Akt isoforms identified RNA metabolism as an Akt target. The phosphorylation of one of the regulators of RNA metabolism (IWS1) was shown to epigenetically regulate alternative RNA splicing. The role of other Akt targets in RNA processing is under investigation.

2:05 Using Ovality to Predict Nonmutagenic, Orally Efficacious Pyridazine Amides as Cell-Specific Spleen

Matt Lucas, Ph.D., Director, Medicinal Chemistry, Discovery Chemistry and Pharmaceutical Research, Cubist PharmaceuticalsTyrosine Kinase Inhibitors’ inhibition of spleen tyrosine kinase (SYK) has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases. The structure-guided optimization of pyridazine amide SYK inhibitors will be presented, along with an approach that led to the successful identification of non-mutagenic examples with reduced cardiovascular liabilities.

EMERGING GENE FAMILIES & CHALLENGING TARGETS

2:35 Solute Carrier Proteins as a Potential Source of New Drug Targets

David Hepworth, Ph.D., Senior Director, Biotherapeutics Chemistry, Worldwide Medicinal Chemistry, PfizerSolute carriers (SLCs) are biologically important proteins that control movement of small molecules and ions across membranes. While the SLC family appears to be generally small molecule druggable and is similar in size to the Class A GPCRs, the number of drug targets is currently around 10x fewer. The presentation explores this paradox and provides an overview of the current status of SLC drug discovery.

2:55 Targeting IAP and BCL Protein-Protein Interactions with Small Molecules: Lessons LearnedBrian Aquila, Ph.D., Associate Director, Medicinal Chemistry Oncology Research, AstraZeneca

3:15 Targeting the Arginine MethyltransferasesKenneth W. Duncan, Ph.D., Associate Director, Molecular Discovery, Epizyme, Inc.

3:35 Modern Drug Research Informatics Applications

Sponsored byto CNS, Infectious, Neglected, Rare,

and Commercial DiseasesBarry Bunin, Ph.D., CEO, Collaborative Drug Discovery (CDD)A modern approach to drug discovery informatics in 5 collaborative case studies showcasing the CDD Vault will be explored. The CDD Vault manages biological and chemical private data securely with external data.




7:00 Close of Day

THURSDAY, JUNE 11

COVALENT AND IRREVERSIBLE INHIBITORS8:35 Chairperson’s RemarksByron DeLaBarre, Ph.D., President & Chief Scientist, The Consulting Biochemist LLC

8:45 Covalent Inhibitors as an Approach for Challenging TargetsAtli Thorarensen, Ph.D., Research Fellow, BioTx Medicinal Chemistry, PfizerCovalent inhibitors provide potential solutions to this difficult target space, but bring additional challenge in medicinal chemistry design due to inhibitors intrinsic chemical reactivity. This talk will provide an overview of selective covalent drug discovery efforts and what key insights are required for successful covalent drug design.

9:05 Discovery of Covalent Inhibitors of Nedd4-1 Ubiquitin Ligase: First-in-Class Covalent Inhibitor of HECT E3s

Alexander Statsyuk, Ph.D., Assistant Professor, Chemistry Department, Northwestern UniversityWe developed a novel fragment-based drug discovery technology: irreversible tethering. We used this to discover a covalent small molecule inhibitor of Nedd4-1 ubiquitin ligase. We will discuss the mechanism of action of Nedd4-1 inhibitor, such as switching Nedd4-1 mediated polyubiquitin chain growth from processive to distributive.

HIT GENERATION & DISCOVERY TECHNOLOGIES:

DNA-ENCODED LIBRARIES, PHENOTYPIC SCREENS & BEYOND

9:25 Direct and Synergistic Inhibition of the HCV NS5A Replication Complex

Makonen Belema, Ph.D., Senior Principal Scientist, Discovery Chemistry, Bristol Myers Squibb Co.The NS5A protein plays multifunctional roles in the hepatitis C virus replication cycle, and its inhibitors are integral components of a promising combination of HCV therapies that secured regulatory approvals recently. Key aspects of the medicinal chemistry effort that optimized a phenotype screen hit to the first-in-class NS5A inhibitor daclatasvir and highlights of mode-of-action studies that revealed considerable synergistic interaction between two distinct classes of NS5A-interacting molecules will be discussed.

9:55 Hit Generation Technologies – From DNA-Encoded Libraries & Phenotypic Screens, to New Chemical SpaceJörg Holenz, Ph.D., Director, Discovery and Preclinical Sciences, Project Leader, AstraZeneca Pharmaceuticals LPLead Generation is defining the quality of chemical assets and - given this importance - has undergone significant changes. New hit generation techniques have been added to the pool, and only by cleverly combining these, the challenge to drug novel demanding targets will be met. This lecture will present learnings from successful lead generation case histories.

10:15 Accounting for Water Energetics in Drug Design

Sponsored by

Woody Sherman, Ph.D., Vice President, Applications Science, SchrödingerWater plays a ubiquitous role in biology and is critical in understanding molecular recognition. While the importance of water is greatly appreciated, a detailed understanding of how to incorporate water into the drug design process has been elusive. For example, crystallography provides the location of a subset of water molecules but cannot place waters throughout the entire binding site. We present strategies for deciding whether it is better to displace, avoid, or bridge a given water molecule once insight into hydration site energetics are in hand.



Mastering Medicinal ChemistryTwelfth Annual


11:30 Triage of High-Throughput Screening Hits: A PAIN in the AssayJonathan B. Baell, Ph.D., Director, Australian Translational Medicinal Chemistry Laboratory and Professor, Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Science, Monash Institute of Pharmaceutical SciencesMathematically, a standard hit rate of say 0.7% necessarily furnishes more false positives from a high-throughput screen than the few (if any) real ligands for that target that may lurk within the set of hits identified. This talk will outline some personal experiences and reflections along with advice on how to efficiently identify problematic screening hits.

WATER IN DRUG DISCOVERY: COMPUTATIONAL & NEXT GENERATION DESIGN

11:50 Time-Average Solvation Distributions in Drug Design: A Holistic Approach to Drug Discovery, from Binding Kinetics to Dynamic ModelingJosé Duca, Ph.D., Global Head, Computer-Aided Drug Discovery, Novartis Institutes for BioMedical Research, Inc.Our lab has developed a theory from first principles that links solvation to binding kinetics at a molecular level. We use a comprehensive approach to design chemical matter with optimized pharmaco(binding)kinetics, redefining the role of computational medicinal chemistry in drug discovery.

12:10 pm Designing Water-Soluble Molecules in Drug DiscoveryMichael A. Walker, Ph.D., Principal Scientist, Medicinal Chemistry, Bristol-Myers Squibb Pharmaceutical Research and DevelopmentA number of strategies have been applied by medicinal chemists in order to rationally design molecules which exhibit appropriate solubility. A majority of these approaches are focused on reducing the hydrophobicity of the molecule. This talk will provide examples where solubility was increased in unexpected ways.


property-based

DRUG DESIGNin medicinal chemistry

Driving Drug Discovery Success by Designing Right Physicochemical and Biophysical Properties


Suggested Event Package:June 9 Short Course*: Drug Metabolism and Its Impact on Decisions in Drug Discovery & Development

June 9 Dinner Short Course*: Understanding and Dealing with Drug Disposition in CNS

June 10-11: Mastering Medicinal Chemistry Conference

June 11-12: Property-Based Drug Design in Medicinal Chemistry Conference

June 11 Dinner Short Course*: Optimizing Physical Properties of Molecules to Achieve High-quality Clinical Candidates* Separate registration required.

THURSDAY, JUNE 11


PROPERTY-BASED STRUCTURE DESIGN CONSIDERATION FOR NEW & NON-TRADITIONAL

MOLECULES2:00 Chairperson’s Opening Remarks

«

2:05 KEYNOTE PRESENTATION: EXPLORING MACROCYCLES FOR DRUG DISCOVERY: NOVEL LEAD SERIES FOR CHALLENGING PROTEIN-PROTEIN INTERACTIONSNick Terrett, Ph.D., CSO, Ensemble Therapeutics Corp.Macrocycles are found widely in nature and several are marketed as drugs with good drug-like properties. This presentation will

illustrate how Ensemble can rapidly generate millions of synthetic macrocycles using DNA-programmed chemistry, and how they are efficiently screened against protein-protein interaction targets to identify hit compounds and SAR. The novel approach will be illustrated with successful examples of lead discovery programs, including the discovery of novel XIAP and IL17A antagonists.

2:35 Property- and Fragment-Based Design Considerations for Protein-Protein Interaction Targets, a Case StudyChristopher N. Johnson, Ph.D., CChem FRSC, Director, Medicinal Chemistry, Astex PharmaceuticalsAstex has successfully applied fragment-based drug design to protein-protein interaction targets. Key factors in this success have been (i) detailed structural understanding of binding interactions between fragment and target protein via x-ray crystallography and (ii) rigorous control of physicochemical properties. The approach is exemplified by Astex’s Inhibitor of Apoptosis Protein (IAP) project, where potent dual antagonists of XIAP and cIAP1 were identified, having in vivo anti-tumor activity.

3:05 Computational Design for Improving ADME Properties of Peptidic MacrocyclesAlan M. Mathiowetz, Ph.D., Associate Research Fellow, Worldwide Medicinal Chemistry, Pfizer, Inc.A great deal of progress has been made in recent years in elucidating design principles for achieving favorable ADME properties in Beyond Rule-of-5 macrocycles. Many of the important principles, such as minimization of exposed polar surface area to improve permeability, are dependent upon the overall 3D structure, which can be computationally predicted and confirmed experimentally. Here we present computational approaches and property/ADME trends seen in a variety of interesting macrocyclic chemotypes.



DESIGNING MOLECULES WITH BETTER DELIVERABILITY AND TARGETING

4:45 Optimizing Brain Exposure in CNS Drug DiscoveryRuben Alvarez Sanchez, Ph.D., Head, Pharmaceutical Profiling, Drug Disposition and Safety, F. Hoffmann-La RocheFor drugs actively transported across the blood-brain barrier, unbound plasma and unbound brain concentrations differ to an extent that is commonly unknown. We report on approaches to assess and predict unbound brain concentration for P-gp substrates and how they can be utilized in early CNS drug discovery to enhance the understanding of PK/PD relationships and support a clinically meaningful compound optimization.

5:15 Inhalation by Design: Approaches towards Designing Drug Candidates for Lung DiseasesPeter Jones, Ph.D., Senior Principal Scientist, Medicinal Chemistry-Inflammation and Remodelling, Pfizer, Inc.Designing compounds with suitable properties for inhalation present unique challenges to the medicinal chemist. This talk will discuss a number of programs from within Pfizer that have addressed this issue, across numerous target classes, to produce inhaled candidate drug molecules for the treatment of various lung diseases – Inhibition of GPCRs, PDEs and Kinases have been targeted successfully via this approach.

5:45 Discovery of Asunaprevir (BMS-650032): An Approved NS3 Protease Inhibitor for the Treatment of Hepatitis CPaul Scola, Ph.D., Research Fellow & Group Leader, Department of Virology Chemistry, Bristol-Myers Squibb Research Co.Hepatitis C Virus (HCV) infection is an insidious liver disease that affects more than 170 million people worldwide. The HCV NS3/4A protease is an essential enzyme for viral replication and, as such, has been validated as a target for anti-HCV therapy in clinical trials. In this presentation, the discovery of BMS-650032, a potent and selective inhibitor of the NS3/4A enzyme, recently approved for treatment of HCV, will be described. Highlights of this discovery process include the design of the acylsulfonamide chemotype, as well as optimization of ADME and toxicology properties within this chemical series.

6:15 Close of Day

FRIDAY, JUNE 12


PREDICTION AND EVALUATION OF DRUG PROPERTIES

8:35 Chairperson’s RemarksTerry Richard Stouch, Ph.D., President, Science for Solutions, LLC


Fourth Annual


Property-Based Drug DesignFourth Annual


«

8:45 FEATURED PRESENTATION: PROPERTY-BASED MOLECULAR DESIGN: WHERE NEXT?Peter Kenny, Ph.D., Visiting Scientist, NEQUIMED-IQSC, University of SãoI will draw the distinction between hypothesis-driven and prediction-driven molecular design before questioning some of the assumptions commonly made in drug discovery. Alternatives

to the octanol/water partitioning system will be discussed and relationships between structures will be outlined as a framework for analyzing biological activity and physicochemical properties.

9:15 Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical CandidatesJan Kihlberg, Ph.D., Professor, Department of Chemistry, BMC, Uppsala University, SwedenAnalysis of drugs and clinical candidates having MW >500 Da demonstrate significant opportunities for discovery of cell permeable and orally bioavailable drugs in physicochemical space far beyond the rule of 5 (bRo5). As compared to Ro5 compliant drugs, those bRo5 may modulate different kinds of targets, in particular ones having flat and groove shaped binding sites. Interestingly, macrocycles appear to have features that provide special opportunities in bRo5 drug space.



11:00 Known Unknowns in Drug Discovery DataTerry Richard Stouch, Ph.D., President, Science for Solutions, LLCData drives Drug Discovery research at all levels and determine the outcome of many thousands of decisions that govern the progress, success, or failure of any one project. Yet, even the ‘experimental’ error of this data is often unknown, under-utilized, or unconfirmed and the actual error has been shown to be even larger that that. This includes physical property data as well as that from assays, biomolecular structure determination, and computational modeling. These errors, their magnitude and genesis will be discussed with a eye toward informed decision making.

11:25 Physicochemical and Biomimetic Properties to Guide Lead OptimizationKlara Valko, Ph.D., DSc, FRSC, Senior Scientific Investigator, UK Analytical Chemistry, RD Platform Technology & Science, GSKMeasurements of physicochemical and biomimetic properties in early drug discovery are used for the estimation of in vivo distribution and drug efficiency. The Drug Efficiency Index (DEI) (potency plus drug efficiency) has been shown to be proportional to receptor occupancy. Simultaneous optimization of potency and drug efficiency can help guide candidate selection toward compounds of increased quality and with reduced chance of later stage failures.

11:50 pm Hepatobiliary Drug Transport: Predicting and Optimizing PharmacokineticsManthena Varma, Ph.D., Senior Principal Scientist, Pharmacokinetics Dynamics & Metabolism, Pfizer, Inc.Hepatobiliary transport is a major disposition pathway, and estimating its contribution to the total systemic clearance is extremely valuable for predicting clinical pharmacokinetics and understanding the possible mechanisms of hepato-biliary toxicity and potential drug-drug interactions. Furthermore, the clinical importance of hepatic drug transporters has attracted potential design strategies to support liver targeting – a key approach to maximizing the potential therapeutic index of a compound. Early assessment of drug exposure (PK) is challenging in this space given the limited information regarding the specific transporter expression levels, lack of established IVIVE and lack of sizable datasets. This presentation provide insight into the hepato-biliary transport with relevance to exposure optimization and the current understanding of the physicochemical and structural drivers in order to facilitate rational drug design.

12:15pm Phosphatidylcholine Affinity Chromatography and Link to Compound Promiscuity, Non-Specific Binding and Phospholipidosis AssessmentJohn Reilly, Ph.D., Senior Research Investigator, Global Discovery Chemistry, Novartis Institute of Biomedical ResearchIn this work, a high throughput chromatographic phosphatidylcholine (PC) affinity assay has been demonstrated to offer an insight into the prediction of compound promiscuity, non-specific binding and phospholipidosis-inducing potential (PLIP) of pharmaceuticals. Results will include >1000 compound study comparing PC affinity to generic compound promiscuity “Target Hit Rate” assay and the benefit of this approach over cLogP. Results will also be presented on how his assay has been a useful tool to predict for non-specific binding for PET ligand tracers and PLIP.



1:30 Session Break

DESIGNING PROPERTIES TO OVERCOME CHALLENGES IN DISCOVERY, DEVELOPMENT &

CLINIC2:00 Chairperson’s RemarksJan Wahlstrom, Ph.D., Director, Pharmacokinetics & Drug Metabolism, Amgen, Inc.

2:05 A Systems Pharmacokinetics Approach to the Optimization of Drug Properties to Help Maximize Therapeutic Index: On the Quantitative Prediction of Unbound Tissue Distribution and its Implication for Drug DesignAvijit Ghosh, Ph.D., Director, Mechanism Based Drug Disposition Pharmacodynamics and Metabolism, Janssen R&DIn this work, we leverage a mathematical model of the underlying physiochemical properties of tissues and physicochemical properties of molecules to support the development of hepatoselective glucokinase activators. A case study using this approach in the development of hepatoselective glucokinase activators via organic anion-transporting polypeptide–mediated hepatic uptake and impaired passive distribution to the pancreas is described.

2:35 Utilizing Physiologically Based Pharmacokinetic Modeling to Inform Formulation and Clinical DevelopmentJan Wahlstrom, Ph.D., Director, Pharmacokinetics & Drug Metabolism, Amgen, Inc.Physicochemical properties and early ADMET assays guide chemotype evaluation and rational scaffold alteration. This presentation will focus on the integration of these approaches with physiologically based pharmacokinetic modeling (PBPK) to enable the prediction of clinical outcomes and to optimize selection of formulation.

3:05 The Discovery and Development of an HIV-1 Attachment Inhibitor Clinical CandidateKap-Sun Yeung, Ph.D., Principal Scientist, Discovery Chemistry, Pharmaceutical R&D, Bristol-Myers Squibb Co.The inhibition of the attachment of the HIV-1 viral glycoprotein gp-120 to the host cell receptor CD4 during the first step of the viral entry represents a novel antiretroviral approach. This talk will discuss the modifications made by medicinal chemists based on clinical feedback from multiple compounds, discuss a successful prodrug approach, and describe formulation development leading to a clinical candidate that is currently progressing to Phase III studies.




June 9 Dinner Short Course*: Imaging in Cancer Research: Key Applications, Modalities and Strategies

June 10-11: Chemical Biology for Target Validation Conference

June 11-12: Chemical Proteomics for Target Validation Conference


WEDNESDAY, JUNE 10


PHENOTYPIC SCREENING, TARGET IDENTIFICATION AND MOA OF NOVEL BIOACTIVE PROBES

8:00 Chairperson’s Opening RemarksIván Cornella-Taracido, Ph.D., Senior Principal Scientist, Discovery Chemistry, Merck

8:05: Chemical Probe Libraries to Explore and Validate Novel BiologyIván Cornella-Taracido, Ph.D., Senior Principal Scientist, Discovery Chemistry, MerckChemical probes, drug-like or not, have been used for years to identify new therapeutic targets as well as to perform validation studies directed to assess their efficacious engagement and pharmacological modulation. Herein I will elaborate on the physicochemical and biological features of a good tool compound, review historical work to assemble a comprehensive, properly annotated, collection of optimal chemical probes and discuss its use towards exploratory phenotype-driven biology (target discovery) and target validation.

8:35: A Trigger Based Selectivity Mechanism of Cell Death Identified through Chemical GeneticsDeborah Rothman, Ph.D., Investigator III, Chemical Genetics, Novartis Institutes of Biomedical ResearchPhenotypic drug discovery has gained momentum as a complementary approach to target based drug discovery in the last decade. Though a phenotypic drug discovery approach, we have identified the N-BICs series of small molecules, which selectively kill a subset of cancer cells. Using multiple profiling tools and techniques, we identified the mechanism of selectivity to be activation of the compounds by high cellular expression of a phase II metabolic enzyme. Additionally, we show that the compounds covalently modify cellular proteins as part of their efficacy mechanism yet are efficiently cleared from animal models.

9:05 Sulfonyl Fluoride Chemistry for Target Validation, Identification and Other Applications in Chemical BiologyLyn Jones, Ph.D., Head, Chemistry, Chemical Biology & Rare Diseases, PfizerI will describe the first rational design and synthesis of sulfonyl fluoride covalent probes that specifically target reactive tyrosine residues in a protein binding site. Subsequent development of a clickable covalent inhibitor of the mRNA/miRNA metabolizing enzyme DcpS enabled the measurement of target engagement in human primary cells for the first time. This technology validated DcpS as a bona fide target protein of a series of diaminoquinazoline derivatives and the broader utility of sulfonyl fluoride chemical probes in chemical biology will be described.



CHEMICAL TOOLS MODULATING GENE EXPRESSION AND PROTEIN HOMEOSTASIS

10:50 Featured Presentation: Targeted Protein Degradation of Pathological ProteinsAndy Crew, Ph.D., Vice President, Chemistry, ArvinasBased on an ‘event-driven’ paradigm, targeted protein degradation offers a novel and broad mechanism to irreversibly inhibit protein function, namely, the intracellular destruction of target proteins. This is achieved via small molecule mediated recruitment of the target proteins in question to the E3 ligase component of the UPS cellular quality control machinery. The application of the Arvinas degradation platform to identification of potent degraders of TBK1 will be described.

11:20 Targeting the Stress Chaperome in Disease, Diagnosis and TreatmentGabriela Chiosis, Ph.D., Associate Member and Lab Head, Molecular Pharmacology and Chemistry, Sloan Kettering Institute; Associate Attending, Department of Medicine, Memorial Sloan Kettering Cancer CenterNormal cellular physiology is maintained by the coordinated action of the chaperome, a network of molecular chaperones as well as co-chaperones and folding enzymes. By using innovative methods, we develop small molecule chemical tools specifically targeted to the stress chaperome; these act as “sensors” of the chronic stress, and in turn, of the chronic stress-associated proteome. I will discuss how by the use of these unique tools we aim to understand, diagnose and treat cellular processes associated with chronic stress.

11:50 Chemical Modulation of Chromatin StructureJun Qi, Ph.D., Senior Research Scientist, Bradner Lab, Department of Medical Oncology, Dana-Farber Cancer Institute



NOVEL SYNTHETIC METHODS FOR MODULATION OF BIOLOGICAL PROCESSES

1:30 Chairperson’s RemarksAlexander Statsyuk, Ph.D., Assistant Professor, Department of Chemistry, Northwestern University

1:35 Small Molecules to Engineer and Explore Human ImmunityDavid A. Spiegel, Ph.D., M.D., Professor, Department of Chemistry, Yale UniversityResearch in the Spiegel Laboratory utilizes techniques and insights from organic chemistry to modulate and/or create immunological function, an area termed “Synthetic Immunology.” This talk will discuss our recent work toward novel paradigms for immunotherapy by developing and characterizing synthetic constructs that harness immune responses. Specific topics to be discussed will include the rational design and biological characterization of immunomodulatory small molecules, as well as applications in areas ranging from cancer to infectious disease.


Second Annual


Chemical Biology for Target ValidationJune 10-11, 2015 | Boston, MASecond Annual

2:05 Spliceosome Modulation for the Treatment of Mutant SF3B1 CancersGregg F. Keaney, Ph.D., Senior Scientific Investigator, Medicinal Chemistry, H3 BiomedicineThis presentation will describe how the pladienolide natural products were originally identified to interact with the spliceosome through target identification cross-linking experiments, and how recently-discovered SF3B1 mutations in chronic lymphocytic leukemia (CLL) and myelodysplastic syndrome (MDS) represent a novel biological target for therapeutic intervention. The total synthesis of 6-deoxypladienolide D, a structurally-complex macrocyclic natural product, along with its biological activity in a suite of mutant SF3B1 assays will be described.

2:35 Discovering and Validating Drug Targets Using Synthetic Binding Shohei Koide, Ph.D., Professor, Department of Biochemistry and Molecular Biology, The University of ChicagoWe have developed “Monobodies,” synthetic binding proteins that can be introduced into cells as genetically encoded protein. Remarkably, Monobodies to diverse target proteins are almost always inhibitors of their functions. Like small-molecule drugs, Monobodies modulate endogenous targets by binding them. Therefore, investigation of cellular effects of Monobodies and of the structural basis of Monobody-target interactions accelerates target validation and the discovery of potentially druggable sites. I will discuss our approach as applied to signal transduction and epigenetics.

3:05 High-Throughput Generation of Synthetic Peptides Modulating Enzyme FunctionSachdev Sidhu, Ph.D., Professor, Donnelly Centre for Cellular & Biomolecular Research, Department of Molecular Genetics, University of TorontoPeptide ligands are promising small-molecule therapeutic candidates for devastating diseases such as cancer. In principle, some natural proteins could be used as therapeutic agents, but their target binding affinities often precludes their use in a clinical setting. Using a phage display strategy and libraries of variant proteins designed based on crystal structure information, we can evolve high affinity variants that show increased binding affinity and improved activity compared to the wild type proteins.

3:35 Modeling Peptide Therapeutics/A Case Study Sponsored byIrene Meliciani, Ph.D., Head, Sales & Business Development, Intelligent PharmaThe identification of small molecules which can mimic peptides has greatpotential in overcoming difficulties associated with synthesis, or unfavorablephysical properties. Through a case study we applied our ligand-based virtualscreening to determine the similarity of a peptide to a set of small moleculesthat were experimentally validated.





7:00 Close of Day

THURSDAY, JUNE 11


KEYNOTE SESSION: TECHNOLOGICAL INNOVATIONS

8:35 Chairperson’s RemarksLyn Jones, Ph.D., Head, Chemistry, Chemical Biology & Rare Diseases, Pfizer

8:45 From Yeast to Human Neurons and Back Again: Powerful Platforms for Chemical Biology and Target ValidationSusan Lindquist, Ph.D., Professor, Biology, MIT; Investigator,

Howard Hughes Medical InstituteTaking advantage of the highly conserved biology of protein folding and trafficking in eukaryotic cells, we have created yeast models of human neurodegenerative diseases that recapitulate the basic pathological processes disrupting protein homeostasis. Significantly, each yeast model exhibits cellular toxicity through a different mechanism. The unique advantage of these models is the ability to perform ultra-highthroughput screening of chemical compound libraries. Hits from these yeast screens rescue patient-derived neurons. With this validation, we return to yeast and use the power of yeast genetics to identify targets. This lecture will discuss recent successes and the future promise of these yeast-to-neurons-to-yeast platforms.

9:30 FITGE-Based Target Identification for the Connection of Rational Drug Discovery with Phenotypic ScreeningSeung Bum Park, Ph.D., Professor, Chemistry, Seoul National University

We developed a new target identification platform, FITGE, which aims to preserve protein-small molecule interactions under the intact cellular environment. I will report a phenotype-based discovery of initial hits that enhance the cellular glucose uptake in myotubes and adipocytes Identification and rational optimization of initial hits can generate lead compounds with high potency for PPARg transactivation and cellular glucose uptake. I will also present our current efforts on the development of novel neuroinflammatory agents from phenotypic screening and target ID.



CASE STUDIES IN CHEMICAL BIOLOGY TARGETING PPIs AND ALLOSTERY

11:30 Novel Probes for E3 Ligases: pH Cleavable Photocrosslinkers to Map E2/E3 Ligase PPI Interface and UbiFlu Novel Fluorescent ProbesAlexander Statsyuk, Ph.D., Assistant Professor, Department of Chemistry, Northwestern UniversityWe will present our work toward the development of chemical probes to study the biochemistry and pharmacology of E3 ubiquitin ligases. First we have developed a novel class of pH-cleavable, minimalist photocrosslinkers that can be installed anywhere on the surface of the E2 enzyme using cysteine chemistry. The second part of this talk will outline the invention of a novel class of fluorescent activity based probes for E3 ligases called UbiFlu.

12:00 pm Not All mGluR PAMs Are Created Equal: Designing the Right Allosteric Ligand for Your Clinical IndicationDario Doller, Ph.D., Director, Discovery Chemistry & DMPK, Global Head of Chemical Biology, Lundbeck Research USAAllosteric modulation of glutamate-sensing metabotropic receptors (mGluRs) has the potential to provide new therapies for the most debilitating CNS diseases (AD, PD, MS). Advances in our understanding of the chemical biology of these receptors has enabled the characterization of ligands with distinct phenotype. We will disclose new results in the area of mGlu4 positive allosteric modulation, including careful characterization of different tool compounds.




June 9 Dinner Short Course*: Imaging in Cancer Research: Key Applications, Modalities and Strategies

June 10-11: Chemical Biology for Target Validation Conference

June 11-12: Chemical Proteomics for Target Validation Conference


THURSDAY, JUNE 11


OPENING KEYNOTE SESSION: TECHNOLOGICAL INNOVATIONS

2:00 Chairperson’s Opening RemarksMarkus Schirle, Ph.D., Senior Investigator, Developmental and Molecular Pathways/Chemogenetics, Novartis Institutes for BioMedical Research

2:05: BioPlex 1.0: An Orfeome-Based, Mass Spectrometry-Driven, Human Protein Interaction Network

Steven P. Gygi, Ph.D., Professor, Cell Biology, Harvard Medical SchoolWe report a scalable affinity-purification mass spectrometry (AP-MS) platform and identify interacting partners for 2,594 proteins in HEK293T cells. The resulting network (BioPlex 1.0) contains 23,744 interactions, 86% previously unknown, among 7,668 proteins. This lecture will highlight network’s construction and its insights into human disease. Within two years, the platform described here will be used to determine interacting partners from a complete pass through the Orfeome collection (~13,000 human genes).

2:50 Mass Spectrometry-based Proteomics in Preclinical Drug DiscoveryBernhard Kuster, Ph.D., Professor, Co-Founder and Chair, Proteomics and Bioanalytics, Technische Universität München,

OmicScouts GmbHPreclinical stages in the drug discovery process require a multitude of biochemical and genetic assays in order to characterize the effects of drug candidates on cellular systems and model organisms. Dramatic technological improvements in mass spectrometry-based proteomic and chemical proteomic strategies substantially facilitate decision-making throughout the drug discovery process. Here, we highlight proteomic approaches suitable for preclinical drug discovery and illustrate the potential of exciting recent developments.



PROTEOMICS-ENABLED DISCOVERY4:45 Proteomics as a Contributing Technology in Drug DiscoveryKieran Geoghegan, Ph.D., Research Fellow, Pfizer, Inc.The relationship of proteomics to drug discovery continues to be explored and developed. Among the trends driving interest in such approaches are the targeting of proteins with deep controlling effects on cell metabolism, a revived interest in drugs that form covalent bonds with their targets, and the need to deconvolute the action of potent compounds for which no molecular target is known. All aspects of the continuum existing between classical proteomics and chemical biology offer potential to elucidate highly valued new information about drug action.

5:15 Tracking Cancer Drugs in Living Cells by Thermal Profiling of the Proteome Marcus Bantscheff, Ph.D., Head, Technology, Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline

5:45 Proteomics-Based Methods for In-Depth Analysis of Key Molecular Events in TumorogenesisJarrod Marto, Ph.D., Department of Biological Chemistry and Molecular Pharmacology, Dana-FarberProteomics-based methods provide a highly parallel readout of multiple biologically relevant events in a single experiment. Collectively these data provide a detailed view of key molecular mechanisms in cancer initiation and progression and can also facilitate drug target discovery and improved characterization of small molecule-based therapeutics.

6:15 Close of Day

FRIDAY, JUNE 12


CHEMOPROTEOMIC STRATEGIES FOR INHIBITOR DEVELOPEMENT

8:35 Chairperson’s RemarksAlexander Statsyuk, Ph.D., Assistant Professor, Chemistry, Northwestern University

8:45 Chemical Proteomic Strategies to Investigate Reactive CysteinesEranthie Weerapana, Ph.D., Assistant Professor, Chemistry, Boston CollegeWe have applied chemical proteomics to identify and characterize functional cysteines in the human proteome. By combining small-molecule probe synthesis with mass spectrometry-based proteomics, we have identified reactive and functional cysteines that can be targeted for covalent inhibitor development. Our small-molecule probes act as pharmacological modulators of diverse protein activities.

9:15 Serendipitous Discovery of the Selective Inhibitor of the Ubiquitin System Using Chemoproteomic ApproachesAlexander Statsyuk, Ph.D., Assistant Professor, Chemistry, Northwestern UniversityWhile designing chemoproteomic probes for UBL proteins based on covalent Nedd8 E1 enzyme inhibitor MLN4924, we discovered a molecule ABP3 that potently and covalently labeled ubiquitin and Nedd8 proteins inside A549 cells. The key to this discovery was the use of click chemistry that allowed us to visualize and identify protein targets of ABP3, due to the presence of an alkyne tag in the molecule. Subsequent follow up experiments showed that ABP3 is a potent inhibitor of Nedd8 ubiquitin conjugation in cells, but not SUMO, ISG15, and Ufm1 conjugation.




Inaugural

Chemical Proteomics for Target ValidationJune 11-12, 2015 | Boston, MAInaugural

ADVANCES IN TARGET DECONVOLUTION11:00 Towards Comprehensive Coverage of Drug Target Space in Chemical ProteomicsMarkus Schirle, Ph.D., Senior Investigator, Developmental and Molecular Pathways/Chemogenetics, Novartis Institutes for BioMedical ResearchNon-covalent approaches have been highly successful for certain target classes. However, they have a significantly lower success rate for important target classes that require intact cellular environments. In these cases, covalent strategies such as photocrosslinking-based experiments using live cell treatment have proven to be successful but require careful experimental design and optimization. Our efforts towards a comprehensive chemical proteomics strategy for de novo target deconvolution that includes covalent and non-covalent approaches will be presented.

11:30 Case Strudies in Target Identification and Mechanism of Action in Drug DiscoveryMonica Schenone, Ph.D., Technical and Scientific Leader, Biochemical Target ID, Proteomics Platform, Broad Institute

12:00 pm Small Molecule Profiling by Protein Stability-Based Interaction Proteomics (ProSIP)Kilian Huber, Ph.D., Senior Fellow, Giulio Superti-Furga Laboratory, CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesWe report an unbiased systems-level approach to monitor small-molecule target engagement in live cells based on protein thermal stability and quantitative mass spectrometry. The procedure does not require chemical modification of the compound of interest and in combination with tailored bioinformatic analysis constitutes a powerful means to assess target binding in a physiological context. Protein Stability-based Interaction Proteomics (ProSIP) should allow for the systematic mapping of chemical agents, including metabolites, to their natural partners.

12:30 Utilizing Chemogenomics to Chemoproteomics to Identify and Validate New Targets in Drug DiscoveryErik Hett, Ph.D., Principal Scientist, Chemical Biology, Medicinal Chemistry, PfizerDuring this presentation I will share case studies illustrating the the ultization of gene-family biased small molecule sets in phenotypic screens to identify druggable targets and to enable target identification, as well as ultilzating activity-based protein profiling to deconvolute phenotypic hits.


1:30 Session Break

BIOORTHOGONAL TECHNIQUES FOR LABELLING AND IMAGING

2:00 Chairperson’s RemarksDoug Johnson, Ph.D., Associate Research Fellow, Neuroscience, Medicinal Chemistry, Pfizer

2:05 Tandem Photoaffinity Labeling - Bioorthogonal Conjugation in Medicinal ChemistryDavid Lapinsky, Ph.D., Associate Professor, Medicinal Chemistry, Division of Pharmaceutical Sciences, Duquesne UniversityThis lecture willhighlight recent applications of tandem photoaffinity labeling–bioorthogonal conjugation as a powerful and versatile chemical approach. In particular, recent applications of this strategy towards affinity-based protein profiling (AfBPP), drug target identification, binding ensemble profiling, studying endogenous biological molecules, and imaging applications will be presented. Additionally, recent advances in the development of ‘all-in-one’ compact moieties possessing a photoreactive group and clickable handle will be presented.

2:35 A Modular and Traceless Chemical Method to Locate and Track Endogenous Protein Targets in Live CellsJames Chambers, Ph.D., Assistant Professor, Chemistry, University of Massachusetts, AmherstI will describe out rationale for designing a traceless, chemistry-based probe that allows for tagging endogenous receptors on neurons. The probe combines elements of medicinal chemistry, bio-conjugation, chemical biology, and neurobiology. I will provide a detailed discussion of our design and implementation for our first probe that was targeted to glutamate-gated AMPA receptors. I will then discuss our present efforts to modularize the system.

3:05 Chemoproteomics with Clickable Photoaffinity Probes for Neuroscience Target ID and ValidationDoug Johnson, Ph.D., Associate Research Fellow, Neuroscience, Medicinal Chemistry, PfizerThis talk will describe how we used clickable photoaffinity probes for (off-)target identification/validation and to measure target engagement in live cells for three neuroscience projects at Pfizer. In the first example, we used clickable β-secretase modulator (GSM) photoaffinity probes to determine the target of GSMs within the γ-secretase complex.




For sponsorship and exhibit information, please contact:Joseph VaccaAssociate Director, Business Development781-972-5431 | [email protected]

AbcamAMRIAntiCancer, Inc. AxiogenesisBiomodels, LLCBiopta LtdBruker CorporationCellular Dynamics InternationalChampions OncologyCharles River Chemical Computing GroupCollaborative Drug Discovery (CDD)

Halocarbon Products HybrigenicsIntelligent PharmaInternational Institute for the Advancement of MedicineInvivoSciences, Inc. KIYATEC Inc.Molecular Sensing, Inc. OncodesignOptibriumPersomics USA, Inc. PharmAgra Labs, Inc.

ProQinaseReaction Biology CorporationSchrödinger SCIVAX Life Sciences, Inc. Simulations Plus, Inc.Solid Form Solutions LtdStudylog Systems, Inc.Sygnature DiscoverySynthonixTaconic BiosciencesThe Jackson LaboratoryVisualSonics

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Includes access to 2 conferences or training seminar, excludes short courses Academic, Government, Commercial Hospital-affiliated

Registrations After March 13, 2015 $2,599 $1,179Advance Registration Rate until May 1, 2015 $2,799 $1,279After May 1, 2015 and on-site $2,999 $1,379

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Registrations After March 13, 2015 $1,549 $749Advance Registration Rate until May 1, 2015 $1,749 $829After May 1, 2015 and on-site $1,949 $899 Program Selection: When registering please indicate the one conference you will attend:

June 10-11, 2015 June 11-12, 2015T1A: Novel Preclinical Models in Oncology T1B: Tumor Models for Cancer ImmunotherapyT2A: Translational Imaging in Cancer Drug Development T2B: 3D Cellular ModelsT3A: Targeting GPCRs T3B: Targeting Histone Acetylation

T4A: New Models for Predicting Drug Toxicity T4B: Synergistic Use of Functional Genomic Technologies

T5A: Blood-Brain Barrier TSB: Training Seminar: Applying Pharmacology to New Drug Discovery

T6A: Mastering Medicinal Chemistry T6B: Property-Based Drug Design in Medicinal Chemistry

T7A: Chemical Biology for Target Validation T7B: Chemical Proteomics for Target Validation

SHORT COURSE

Single Short Course $699 $399Two Short Courses $999 $699Three Short Courses $1,199 $899

Please select the short courses you are most likely to attend.

Tuesday, June 9 | 2:00 – 5:00 pm Thursday, June 11 | 7:00 – 10:00 pm (Dinner provided)

SC1: Allosteric Modulators of GPCRs, (PAMs NAMs) SC8: Optimizing Physical Properties of Molecules to Achieve High-Quality

Clinical Candidates SC2: Imaging of Blood-Brain Barrier Function SC9: How to Best Utilize Organotypic 3D Cell Cultures in Oncology SC3: Drug Metabolism and Its Impact on Decisions in Drug Discovery

Development SC10: 3D Printing

Tuesday, June 9 | 6:00 – 9:00 pm (Dinner provided) SC11: PDX Models Update

SC4: Biased GPCR Ligands: Towards Novel Drug Discovery

SC5: Understanding and Dealing with Drug Disposition in CNS

SC6: Navigating the CiPA Landscape SC7: Imaging in Cancer Research: Modalities, Agents and Strategies

CONFERENCE DISCOUNTS

Alumni Discount 20% OffDrug Safety Executive Council (DSEC) Members 25% OffPoster Discount $50 Off

POSTER DISCOUNT ($50 Off) Poster abstracts are due by April 24, 2015 Once your registration has been fully processed, we will send an email containing a unique link allowing you to submit your poster abstract. If you do not receive your link within 5 business days, please contact [email protected].

* CHI reserves the right to publish your poster title and abstract in various marketing materials and products.REGISTER 3 - 4th IS FREE: Individuals must register for the same conference or conference combination and submit completed registration form together for discount to apply.ALUMNI DISCOUNT: Cambridge Healthtech Institute (CHI) appreciates your past participation at World Pharma Congress. As a result of the great loyalty you have shown us, we are pleased to extend to you the exclusive opportunity to save an additional 20% off the registration rate. Please note: Our records must indicate you were an attendee of World Pharma Congress in the past in order to qualify.

Group Discounts are Available! Special rates are available for multiple attendees from the same organization. For more information on group discounts contact David Cunningham at 781-972-5472

*Alumni, DSEC Membership, Twitter, LinkedIN, Facebook or any other promotional discounts cannot be combined. Discounts not applicable on Event Short Courses.

If you are unable to attend but would like to purchase the World Preclinical Congress 2015 CD for $750 (plus shipping), please visit WorldPharmaCongress.com. Massachusetts delivery will include sales tax.

Pricing and Registration Information

June 10-12, 2015 Westin Boston Waterfront, Boston, MA

http://www.healthtech.com/regdetails

http://www.insightpharmareports.com/

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http://www.barnettinternational.com/

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