Drug Discovery through Academic/Industry Collaborations · 2016-02-26 · Allan Jordan Ben Acton Habiba Begum GlaxoSmithKline Phil Chapman Mark Cockerill Emma Fairweather Samantha

Drug Discovery through Academic/Industry Collaborations

Allan Jordan Drug Discovery Unit CRUK Manchester Institute

[email protected]

CRUK-MI Drug Discovery Unit Background

• CRUK Manchester Institute – Specialist cancer research institute core funded by Cancer Research UK

– Fundamental molecular & cell biology through to translational research


• The Christie – Largest oncology treatment centre in Europe

– Ca 40,000 pts per annum

– Largest PhI/II oncology CTU in the world


• Drug Discovery Unit – Focus on niche cancer targets with clear route to clinical evaluation

– Targets include cell metabolic pathways, DNA repair mechanisms and epigenetics

– Access to CRUK-MI investigators

– Access to the clinic and translational medicine

CRUK-MI DDU Group

Target identification: Strategic Considerations

CRUK strategy:

Novel/higher risk

Leverage locality

Target Target validation Feasibility

Target Function Clinical Preclinical Chemistry Biology Competitive

Mutant IDH 1 & 2 2 HO-glutarate onco-metabolite? MonoTx or combo Driver or initiator? Biotech

G6PDH PPP glucose metab, NADPH regulation RTX combo NADPH hypothesis

Ret selective Receptor tyrosine kinase oncogene Thyroid cancer Selectivity vs KDR Academic

TTRAP /Tdp2 DNA repair Topo2 -resistant Margin, hypothesis

POL Q DNA repair RTX combo Margin, hypothesis

IDH1, wild type NADPH regulation? RTX combo Hypothesis?

Malic enzyme pyruvate metab, NADPH regulation RTX combo Hypothesis?

PDK1 growth /proliferation (PI3K /Akt p'way) PTEN null Allosteric inhibitor? Big Pharma

Taspase I suggested downregulator of Usp9x Nothing to go at

Other part of

pathway

MYD88 L265P Adaptor protein CLL

UROD

PSAT1 Phosphoserine aminotranserase

PYCR

PHD3

BBOX1 review in progress

Enolase II

FEN 1 DNA repair

rad54 DNA repair

rad51 DNA repair

EGFRvIII

SCL7A11

6PGDH Metabolism RTX combo NADPH hypothesis

HGDH GBM / AML

PHGDH Metabolism NADPH hypothesis

DNMT1 Methyltransferase

NLK Kinase

MLK1 Kinase

MLK2 Kinase

BMI

RAC1 (P29S mutation)

C-FLIP

ABC transporters

RNF2

JARID1B

H3K4 demethylase Melanoma

IDHrev

reductive carboxylation

PDPK1

Lipid Kinase

Allosteric site best way

forward

ROS1

DNA Repair selectivity selectivity

TET2

AML

RING1B

E3 ubiquitin-protein ligase

HIF1alpha/p300

protein/protein interaction

PARG poly ADP ribose degradation CTX combo / BRCA Hypothesis Awaiting structure

LRP16

nuclear receptor transactivation,

poly ADP-ribose polymerisation Emerging

SNM1a DNA repair Emerging

CHFR ubiquitin ligase Emerging

Aprataxin DNA repair

ALC-1 helicase - chromatin stabilisation CTX/RTX combo Margin?

APLF poly ADP ribose stabilisation Emerging

AAG base excision repair CTX combo Margin?

APG? base excision repair? Emerging

ANG? base excision repair? Emerging

MGMT base excision repair? CTX combo Margin?

APE AP base excision repair CTX combo Margin? Academic

PERK UPR stress response to hypoxia/anoxia RTX combo Hypothesis? CRT hits CRUK portfolio

HIF-1 hypoxic response RTX combo What is mol target? Awaiting hits POM target

Hypox bioreductives, nitromidazole delivery of warhead to hypoxic tumour RTX combo Which warhead?

NQO1,2 active site inhibitor RTX combo Comp chem hits?

NQO1 p53 stabilisation, ROS protection RTX combo Hits?

NQO2 p53 stabilisation, ROS protection RTX combo Hits?

Hypoxic gene profiling West/Harris studies None tractable yet

Stromal infiltration, post therapy Awaiting details

mct-4 carboxylate transporter (eg lactate) Warburg Big Pharma

Sarcosine amino acid methylation Inv /met target

γ-secretase pan-Notch cleavage (GI toxicity) Selectivity vs. notch Merck in clinic

FAK adhesion complex Hypothesis Pfizer in clinic

CD44 - intracellular signal stem cells i-c Target?

CXCR4 stem cells & stroma Big Pharma

LIF stem cells Validation?

BMP6 stem cells Validation?

Notch - selective downstream cell survival /proliferation i-c Target? Feasibility?

Notch, cbf-1 interaction nuclear medaitor of Notch sig. Feasibility?

Integrins /p-Erk growth factor signalling i-c Target? Feasibility?

Wee-1 Big Pharma

HSET CRUK portfolio

No opportunities identified yet



Phosphatases Signalling Selectivity







TG2 - AML oncogene signalling

CD45 phosphatase AML oncogene signalling AML Selectivity vs normal Selectivity

AEP asparagine supply ALL (paeds) AEP as target?

LSD1 Leukemia watch for GSK



mcm2-7 helicase Helicase Target complexity

Target

complexity

CDK Selectivity? Selectivity? Big Pharma

RNA Primase Primase Target complexity

cdc7 CRUK portfolio




MLK4 ser thr Kinase

LZK ser thr Kinase

MCRC strategy:

Lung, melanoma, haems, RTx,

women.

Local PIs

Competition:

Avoid mainstream unless advantage

Consider niches

Areas of biology:

Oncogene addiction, RTx,

Stem cells, DDR, Hypoxia,

Metabolism, Epigenetics

Target identification: Strategic Considerations

Assessing Chemical Tractability

• For emerging targets where the biological validation is

strong, but there is little or no report of small

molecules which interact with the protein, how can we

assess the chemical risk in pursuing the target?

– how do we validate the drugability of the target?

• Ligandability – the ability of a protein target to bind a small molecule with high affinity

Fragment Screening as a Target Selection Tool

• Fragment screening as an approach to quantify ligandability – 1000-compound diverse fragment library – Various screening platforms – biochemical assay, biophysical (SPR, thermal

melt) – Assess against existing targets – use to prioritise future targets

Fragment Screening : Ligandability Assessment

Drug Discovery Today, DOI: 10.1016/j.drudis.2014.12.011

Fragment Screening as a Target Selection Tool

• Fragment screening as an approach to quantify ligandability – 1000-compound diverse fragment library – Various screening platforms – biochemical assay, biophysical (SPR, DSF) – Assess against existing targets – use to prioritise future targets

• Ligandability screening is not Hit finding

– Fragment screening requires orthogonal screening

• (e.g. biophysical binding assays) to confirm hits

– Our ligandability screening is only used to assess chemical feasibility of a target based on hit rates from biochemical screening

• Decision-making data on target prosecution

Fragment Screening : Ligandability Assessment

Extending capabilities through collaboration

• Screening collaboration (mtIDH)

DNA Repair (PARG)

Epigenetics target

(undisclosed)

GSK Collaboration

AstraZeneca Collaborations

PARG - DNA repair target

- AZ HTS

- AZ crystal structure

- AZ hit

- “At risk” progression

CRUK-MI DDU

Progress to agreed criteria

AZ have first right of refusal

mtIDH - Screening agreement

- DDU access AZ HTS

and other screening

facilities

- Orthogonal confirmation

RE-THINKING INTERNAL SCREENING

Assessing Chemical Tractability

• For emerging targets where the biological validation is

strong, but there is little or no report of small

molecules which interact with the protein, how can we

assess the chemical risk in pursuing the target?

• How can we deliver chemical tools to probe (and

validate) emerging biology?

• How can we work directly (and internally) with PIs to address this question in a meaningful way?

The MIDaS Philosophy

PI

• “Manchester Institute Diversity Set” (MIDaS)

• “Diverse, lead-like, tractable library”

– Ideally 10-15k compounds

• Focussed subsets, relevant to research interests of the Institute

– FDA Approved Drugs (~1200 compounds)

– Kinase Collection (~350 compounds)

– Epigentics Collection (~120 compounds)

• Curated compound collection

Baell and Walters, Nature, 25 Sep 14, p481

From the recent literature…

PC-1

PC-2

PC-3

“Clustered Diversity”

PC

-1

PC-2


PC

-1

PC-2


PC

-1

PC-2


The MIDaS Compound Library

• 10.1K compounds in Echo-ready plates

• 0.75mL 20 mM stock for rapid cherry-pick and follow up

• Rapid cluster expansion from commercial sources

• “Attractive” compounds for future chemistry follow-up

Phenix Outputs

Fixed cell

analysis

Live cell

analysis

3D

assays PPIs

Point & Click

Machine Learning

MIDaS Summary

• Diverse and imaginative collaborative undertaking

– Basic and translational scientists

– Core facilities

– Technology and compound vendors

• Interfaces forefront technology with emerging science

– Flexible platform

– Future development and expansion already under discussion

• Multiple potential outputs

– Credible biological tool compounds

– Investigation and elucidation of emerging biology

– Validated, drugable targets for drug discovery efforts…..

Our learning so far…

• Non-traditional Pharma collaborative models can deliver real benefits

– Non-cash transactions

– Recognition of investments-in-kind

– Resources applied where capacities and complimentary expertise exist

• Science is the driver in Pharma collaborations, but not the rate-limiter

– How to best facilitate the business negotiations?

– Progress the science ahead of the deal?

• One size does not fit all…

– We depend upon mutually beneficial partnerships to progress and prosper

– Creativity, flexibility and imagination are keys to success

• Industry collaborations does not just mean Pharma

– Technology collaborations allow enabling science to drive basic science and drug discovery

Acknowledgements

Drug Discovery Unit: Donald Ogilvie

Ian Waddell

Allan Jordan

Ben Acton Habiba Begum Phil Chapman Mark Cockerill Emma Fairweather Samantha Fritzl Nicola Hamilton Sarah Holt Gemma Hopkins Dominic James Nikki March Helen Small Alex Stowell Graeme Thomson Mandy Watson

Colleagues and Collaborators at:

AstraZeneca Discovery Science

AstraZeneca Oncology iMED

Cancer Research Technology Discovery Labs

Cancer Research UK Beatson Institute

Cancer Research UK Manchester Institute

GlaxoSmithKline

LabCyte

Perkin Elmer

Sigma-Alrich

Jonathan Ahmet Kelly Ayton Roger Butlin Niall Hamilton James Hitchin Colin Hutton Stuart Jones Chris Kershaw Alison McGonagle Daniel Mould Rebecca Newton Ali Raoof Kate Smith Bohdan Waszkowycz

Looking for Group Leaders in the following areas:

• Personalised Medicine • Molecular Pathology • Melanoma Immunology • Prostate Cancer • Pancreatic Cancer • Haematological Oncology

Informal enquiries can be addressed to the Director, Professor Richard Marais via [email protected]

• Extensive start up package including: - Own Salary - Up to 5 additional core-funded posts - Generous running expenses - High quality laboratory space • Scope for group expansion through additional external funding • Excellent core facilities

mailto:[email protected]

Documents

Drug Discovery through Academic/Industry Collaborations · 2016-02-26 · Allan Jordan Ben Acton Habiba Begum GlaxoSmithKline Phil Chapman Mark Cockerill Emma Fairweather Samantha