SRI International Biosciences

Drug Discovery

For more than six decades, SRI has been a major provider of drug discovery

and development services to pharmaceutical and biotechnology companies,

academia, foundations, and government agencies. Through collaborations

with partnering companies and organizations, drugs discovered and developed

by SRI include: Halfan® (halofantrine), a malaria treatment; Vidarabine (trade

names VIRA-A and Ara-A), an antiviral drug active against Herpes simplex and

Varicella zoster viruses; Targretin® (bexarotene) and, most recently, Folotyn®

(pralatrexate), SRI cancer drugs to treat various lymphomas.

SRI’s interdisciplinary team combines expertise in molecular biology;

biochemistry; immunology; medicinal, synthetic, and process chemistry;

pharmacology; computer-aided drug design; molecular modeling; and

assay development for drug discovery and preclinical development.

Whether a single, focused study is required or a comprehensive “turn-key”

program, SRI provides the capabilities necessary to assist clients in the

translation of promising therapeutic candidates for indications involving, but

not limited to, infectious disease, oncology, neuroscience, and immunology

and inflammation.

Research on Disease Mechanisms

Clinical Analysis Laboratory

From Idea to IND®

Drug Metabolism, Pharmacokinetics, & Toxicology Services

PreclinicalDevelopment Planning & Regulatory Services

Pharmaceutical Sciences

Drug Discovery

Learn more

Infectious Disease page 5

Immunology & Inflammation page 4

Neuroscience page 6

Oncology / Cancer page 7

AdditionalDiscoveryCapabilities page 7

Target Validation & Assay Development page 2

Lead Identification & Optimization page 3

Leverage SRI’s experience for your success!

Cell- Based Assays

• Cellviability/compound cytotoxicityassays

• Apoptosis

• Autophagy

• RNAi-basedtargetvalidation

• Intracellularpathogenassays

• Cellularreporterassays

Mechanism-Based Animal Models

• Collagen-inducedarthritis

• Spontaneousdiabetes

• Experimentalautoimmune encephalomyelitis

• Inflammatoryboweldisease

• siRNA

Design and Validation of Biochemical and Cellular Screens

• Uniquemolecularlibrariesfortargetscreeningthroughcombinatorial chemistry

SRI has extensive experience in the identification of novel targets, the discovery of new molecules to interrogate those targets, and the elaboration of new molecular entities into lead compounds for clinical evaluation. SRI has successfully played a major role in translating more than 100 small molecules, biologics, and vaccines through Investigational New Drug (IND) applications into Phase I clinical trials.

SRI’s approach to identifying a new target starts by defining its molecular signature with assays such as those listed below or assays developed to address a specific target. Once cell-based effects are established, we can use affinity chromatography, with the compound on a matrix, to pull out and identify proteins that interact with it.

Target Validation and Assay Development

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• Partnershipsforscale-upmanufacturingofdiagnosticreagentsandkits

Proteomics and Metabolomics

• Novelfluorescenceprobesforearlydetectionofdisease

• Shotgunandquantitativeapproaches

• Characterizationofpost-translationalmodifications

• Geneexpressionanalysis

` Reportergeneactivation/repression

` mRNAarraysandmiRNAarrays

Imaging and Analysis

• Specializedhistology

• Immunocytochemistry

• Fluorescencemicroscopy

• Transmissionandscanningelectronmicroscopy

• Quantitativeimageanalysis

• Noninvasivefluorescence,biolumines-cence,andX-rayimagingofrodents

SRI can apply these assays to a broad range of disease mechanisms and therapeutic classes.

Lead Identification and OptimizationSRI’s success in drug discovery is exemplified by our robust drug pipeline, with several marketed drugs, several in clinical and preclinical development, and numerous discovery programs. SRI has helped clients and partners advance well over 100 drugs into patient testing. Our laboratories routinely perform drug discovery through target identification and lead generation, computer-aided drug design, and directed library design to generate new small molecule leads. During lead optimization, our team can enhance the most promising compounds to improve effectiveness, diminish toxicity, and increase absorption.

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Screening Hits to Leads

• Targetidentification

• Mechanismofactionstudies

• High-throughputscreeningofsmall moleculesforinvitroefficacy

• Hitresynthesisandvalidation

• Pharmacophoreidentification

• Computationalmodelingforscaffold optimization

Lead Optimization

• Parallelandfocusedlibrarysynthesis

• StructureActivityRelationships(SAR) development

• NMR-baseddrugdiscovery

• Solubility,lipophilicity,andionizabilitystudies

Custom Synthesis

• Multistepsynthesisofleadcandidates,syntheticintermediates,referencestandards,degradationproducts,ormetabolites

• Parallelandfocusedlibrarysynthesis ofscreeningsets

• Asymmetricsynthesis

• Processdevelopment

• Milligram-to-kilogramscaleup

Radiolabeled Synthesis

• Isotopiclabelingofcomplexmoleculeswithradioisotopes(14C, 3H, 125I, 32P, 33P, 35S)andstableisotopes(13C, 2H, 15N, 18O)

• Developmentofnewsyntheticmethodsforstereospecificisotopelabeling

• Biosyntheticlabelingofcomplex naturalproducts

• Consultingontheapplicationof isotopicallylabeledmolecules

Preformulation

• Physicochemicalandthermal characterization

• Excipientcompatibilitystudies

• High-throughputsolubilityscreening

• In vitrodrugpermeationstudies

Predictive ADMET Assays

• Membranepermeabilityand transporteractivity

• Drugmetabolismassays

• In vivomicrodialysis

• Targetorganandcytotoxicityassays

• Genetictoxicityscreens

• Invivopilotpharmacokinetic andtoxicityscreens

SRI’s Immunology and Inflammation group provides internationally recognized

services through all stages of drug discovery and development. With state-of-

the-art equipment, laboratory, and animal facilities, we can offer turnkey and

customized services to meet your needs, including assay development and

validation, research and drug discovery, preclinical development, and clinical

sample analysis.

Working with our Quality Control and Quality Assurance groups, we routinely

support GLP and cGMP studies.

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Assay Development and Validation

• In vitro and ex vivoassays (cellfunction/receptorbinding assays/compoundscreening)

• In vivoefficacystudies(animal modelsofinflammatorydisease)

• Customandclient-providedassays

• GLP-andcGMP-compliantstudies

Research and Drug Discovery

• In vitro and ex vivoevaluations ofimmunefunction

• Animalmodelsofautoimmunediseasesincludingdiabetes,inflammatoryboweldisease,multiplesclerosis, andrheumatoidarthritis

• In vivoefficacy,includingdesign ofcustomanimalmodels

• Specializedcompoundscreening inimmunecellsfromhumanandanimaltissues

Preclinical Development

• Assessmentofimmunogenicity (cellularandhumoral)

• Sampleanalysisforpharmacokineticsandtoxicokinetics

• Measurementofvaccineefficacy

• Immunotoxicologyevaluation

• Biomarkeranalysis

Analysis of Clinical Samples

• Immunoassays(measurementof biologicsforpharmacokinetics)

• Determinationofimmunogenicity (cellularandhumoral)

Common Techniques

• ELISA

• Cellularproliferationassays

• CytotoxicTLymphocyte(CTL)assay

• Mixed-lymphocytereaction(MLR)

• Clonalexpansionofprimary immunecells

• Flowcytometry(FACS):intracellularandcellsurfacestaining,cellcycleanalysis,andapoptosis

• AutomatedELISpotanalysis

• Magnetic-activatedcellsorting(MACS)

• Electrophoresisandimmunoblotting

• Receptorbindingassays

• DNAandRNAmolecularbiology techniques,eukaryoticcelltransfection

• RT-PCR,qualitativeandquantitative

• Immunohistochemistryand immunofluorescentstaining

Selected In Vivo Models

• Acuteandchroniccollagen-inducedarthritis

• AcuteandchronicDSS,TNBS/ Oxazolone,andspontaneous(IL-10-/-)inflammatoryboweldisease

• Activeandpassiveexperimental autoimmuneencephalomyelitis

• SpontaneousdiabetesinNODmice

REGULATORY/LICENSING APPROVALS

Select AgentsBSL-3 FacilityGLP and cGMP Compliance

Immunology & InflammationImageSources:Dr.Triche.NationalCancerInstitute

Infectious DiseaseInfectious diseases truly represent a global public health challenge; therefore,

the discovery of safe and effective therapeutics is imperative. At SRI, we

bring a wealth of experience and diverse scientific interests to our mission

of creating improved diagnostics, prophylactics and therapeutics for a wide

range of rare and neglected diseases and tropical diseases, and infectious

and biological threat agents, all of which seriously challenge global health.

Our capabilities include medicinal and synthetic chemistry; in vitro assay

development; and in vitro and in vivo drug efficacy screening against toxins

and bacterial, viral, and parasitic diseases (including CDC select agents) up

to BSL3 containment.

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In Vitro Efficacy Models

• Neglected&emergingpathogens

` TB(Mycobacteriumtuberculosis)drugscreening,including XDR/MDRstrains

` Influenzavirusstrains

` Parasiticdiseases,including LeishmaniasisandChagas

• Drug-resistantbacterialpathogens:

` HAandCA-MRSA,Acinetobacterspp.,Klebsiellaspp.,Pseudomonasspp.

• NIAIDcategoryA,BandCpathogensandselectagents:

` B.anthracis,Y.pestis,F.tularensis,Burkholderiaspp,C.burnetii, Brucellaspp.,Chlamydiaspp., Shigellaspp.,Rickettsiaspp., Listeriaspp,Vibriospp.

` Virusesincludingdengue,SARS,arenaviruses,Hantaan,RiftValleyFever,WestNile,Chikungunya,andotherencephalitis-causingviruses

` Toxinsincludingricin,botulinum,shigaandStaphylococcus enterotoxinB

• Food-bornepathogensincluding Salmonellaandenterohemorrhagic E.coli

• Hostresponseprofilesfollowing host-pathogeninteractions

In Vivo Efficacy Models

• Infectiousdiseasemodeldevelopment

• Mouseandferretmodels ofinfluenzainfection

• Smallanimalimaging

• Sepsismodels

Vector Biology

• Insecticideresistance

• Vectorcompetence

• Entomotherapeutics,theapplication ofinsect-derivedcompoundsasnoveltherapies

Customized Assay Development and Screening

Biomarker Discovery

Diagnostic Development

Radioactive Materials Controlled Substances AAALAC Accredited

ImageSources:RockyMountainLaboratories,NIAID,NIH

The Center for Neuroscience at SRI combines world-class basic science with contract research to provide an environment ideal for partnering with clients and for helping advance research and development programs. Our research programs in sleep, cognition, circadian rhythms, pain and addiction demonstrate our expertise using in vivo physiology and pharmacology, behavior, microdialysis, in vitro electrophysiology, neuroanatomy, and differential gene and protein expression techniques in various animal disease models. Our capabilities allow us to determine the efficacy of novel treatments on behavior and physiology, to investigate the neural mechanisms that underlie drug effects, and provide a translational approach to evaluate preclinical findings for CNS disorders.

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Neuroscience

In Vivo Pharmacology and Behavior

• Sleep/wakerecordingsandanalysis

• QuantitativeEEGanalysis

• Electromyogram(EMG)recordings

• Circadianrhythmsassessment

• Infra-reddigitalvideorecording

• Customneurosurgicalcapabilities

• Invivobrainmicrodialysis

• Intrathecaldrugdelivery

• Customperipheralsurgeries

In Vivo Models

• Ourrodentbehavioralmodelsincludebutarenotlimitedto:

` Acuteandchronicpain (hot-plate,tailflick,CCI;SNL)

` Drugaddiction(CCP,drugSA)

` Chronicalcoholism(bottle-choice)

` Motordisorders(rotarodtesting)

` Anxietyanddepression (openfieldtest,light/darkboxes)

` Learningandmemory (Morriswatermaze)

` Geneticmodelsofneurologicaldiseases(narcolepsy,Huntington’sdiseaseandAlzheimer’sdisease)

•Ournonhumanprimates(NHPs)areoperantlytrainedonbasicleverpressingand/orCANTAB™.Commontestassessmentsinclude,butarenotlimitedto:

` Workingmemoryattention

` Impulsivityantidepressantefficacy

` Pharmacokineticsideeffects

` Biochemical

In Vitro Assays

• Opiate(µ, ,k)andNOP

• Dopamine(D1, D2)

• Serotonin (5-HT2A,5-HT2B,5HT3,5-HT4)

• GABA,Benzodiazepine

• Adrenergic( 1, 2, 1, 2 )

• NMDA

• Sigma

• Nicotinicionchannels

In Vitro Neurophysiology and Neuropharmacology

• Brainslicerecordings

• Whole-cellcurrentandvoltageclamprecordings

• Analysisofmembranecurrentsandsynaptictransmission

• Fluorescenceanddifferentialinterfer-encecontrast(DIC)microscopy

• FLIPR®basedcalciumassays

Neuroanatomy

• Immunohistochemistry

• Insituhybridization(radioactiveandnonradioactiveprobes)

• Basichistologyandstainingtechniques

Gene and Protein Expression

• GeneChip®analysis

• Quantitativereal-timepolymerasechainreaction(qPCR)

• RNAisolationandanalysisofspecificbrainregions

In Vivo Microdialysis and Neurotransmitter Analysis

Freely-moving rodent studies can be performed under the following conditions:

• Awakeoranesthetized

• Singleordualprobeplacement

• Localperfusion(reversedialysis)

• Systemicdrugdelivery(IP,IV,PO,SC)orICV

• Combinedwithotherinvivotech-niques(lesionmodels)

• Monitoringotherbehavioralactivities

Quantitative analytical services of biological samples and perfusates are supported by instrumentation from ESA-Dionex, Inc. Our capabilities include:

• Monoamines(NE,DA,5-HT, andallmetabolites)

• Acetylcholine

• AminoacidsandGABA

• Adenosine

Biomarkers upon request

Biomarker Discovery

Diagnostics

Target Validation and Assay Development

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SRI’s Center for Cancer Research offers a collection of assays that can interrogate many cellular pathways. Our experienced staff works together with our clients to ensure that the most effective interdisciplinary approach is applied to their cancer drug discovery projects. We perform every step in the process, from target identification to selection of a candidate for preclinical development.

These integrated processes include: identification and validation of novel targets; development of assays; selection of leads guided by functional assays; exploration of structure-activity relationship (SAR) through medicinal chemistry; and compound optimization through iterative cycles of testing for drug-like properties and potency, finally resulting in identification of a molecule for development.

Oncology / Cancer

ADDITIONAL DISCOVERY CAPABILITIES

In Vitro Efficacy Assays Models

• Proliferation

• Cytotoxicity

• Apoptosis

• Autophagy

• Cellcycleanalysis

• Migrationandinvasion

• Angiogenesis

` Endothelialproliferation,migration,andtubeformation

` Ex ovochickchorioallantoic membraneassay(CAM)

In Vivo Efficacy Models

• Xenograftmodelsbasedonthe followinghumancelllines:

` Breastcancer

` Cervicalcancer

` Coloncancer

` Fibrosarcoma

` Glioblastoma

` Kidneycancer

Noninvasive imaging models

• Orthotopicstudies

` Humanbreastcancermodel

` Humanglioblastoma

` Humanprostatecancermodel

• Metastasisstudies

` Humanbreast

` Humanprostate

` Murinemelanoma

` Multiplemyeloma

Hypoxia Models

• Invitroresponses

• Invivoimagingandanalysis ofhypoxia

` Leukemia

` Livercancer

` Lungcancer

` Medulloblastoma

` Melanoma

` Myeloma

` Neuroblastoma

` Osteosarcoma

` Ovariancancer

` Pancreaticcancer

` Prostatecancer

` Tonguesquamouscarcinoma

• Syngeneicmousemodels

` Colon

` Melanoma

` Pancreaticcarcinoma

• Additionalcommercialcell linesuponrequest

•Radiotherapy

` Combinationefficacystudies

Cell and Molecular Imaging

Reproductive / Hormonal

Diabetes / Metabolic Diseases

Microdialysis Molecular Biology

Angiogenesis

Contact Us

SRI Biosciences 333 Ravenswood Avenue Menlo Park, CA 94025-34931.650.859.3000

Center for Advanced Drug ResearchSRI Shenandoah Valley 140 Research DriveHarrisonburg, VA 228021.540.438.6600

Toll-Free: 1.866.451.5998Email: biosciences@sri.com

www.sri.com/biosciences

Menlo Park Headquarters

SRI International333 Ravenswood AvenueMenlo Park, CA 94025-3493 1.650.859.2000

Washington, D.C.

SRI International 1100 Wilson Blvd., Suite 2800Arlington, VA 22209-3915

1.703.524.2053

www.sri.com

SRI International and Idea to IND are registered trademarks of SRI International. All other trademarks are the property of their respective owners.

Copyright 2011 SRI International. All rights reserved. 02/11

About SRI International BiosciencesSRI Biosciences carries out basic research, drug discovery and drug development, and provides contract services. SRI has all of the resources necessary to take R&D from Idea to IND®—from initial discovery to the start of human clinical trials—and specializes in cancer, immunology and inflammation, infectious disease, and neuroscience. SRI’s product pipeline has yielded marketed drugs, therapeutics currently in clinical trials, and additional programs in earlier stages. In its CRO business, SRI has helped government and other clients and partners advance well over 100 drugs into patient testing. SRI is also working to create the next generation of technologies in areas such as diagnostics, drug delivery, medical devices, and systems biology.

About SRI InternationalSilicon Valley-based SRI International is one of the world’s leading independent research and technology development organizations. SRI, which was founded by Stanford University as Stanford Research Institute in 1946 and became independent in 1970, has been meeting the strategic needs of clients and partners for more than 60 years.

Perhaps best known for its invention of the computer mouse and interactive computing, SRI has also been responsible for major advances in drug discovery and development, networking and communications, robotics, advanced materials, atmospheric research, education research, economic development, national security, and more. The nonprofit institute performs client-spon-sored research and development for government agencies, busi-nesses, and foundations. SRI also licenses its technologies, forms strategic alliances, and creates spin-off companies.