Chemical Probes for Pre-Competitive Target Validation

Paul Brennan

SGC OxfordTarget Discovery Institute

Nuffield Department of Medicine University of Oxford

OSP21 September 2015

Paul, S.M., et al., How to improve R&D productivity: the pharmaceutical industry's grand challenge.

Nat Rev Drug Discov 2010 9(3) 203-214

Attrition

Was it the right Target for the Disease?

No, 66% of the time

Paul’s AttritionPharma Year Target Molecule Outcome

AmgenThousand Oaks, California

2003 - 2005 PLK inhibitors for oncology Safe, effective

moleculeCompetition too far ahead

Oncology Kinase Target Safe, effective molecule

Ineffective in animal models

PfizerSandwich, Kent

2005 -2011

Alpha1a CNS partial agonist for overactive bladder

Could not achieve profile

5HT2C CNS agonist for mixed incontinence, FSAD, obesity

Safe, effective molecule

Therapeutic area dissolved

Asthma GPCR Target Safe, effective molecule

Competition too far ahead

Asthma Enzyme Target Safe, effective molecule

Therapeutic area dissolved

Pain Ion Channel Target Early leads Competition too far ahead

Allergic Rhinitis GPCR Target Safe, effective molecule

Research site dissolved

INTRODUCING THE SGCThe SGC is a public-private partnership with a mandate to place protein structures of relevance to human health into the public domain, free from restrictions on use. Focus on proteins from human and human parasites.

• To promote drug discovery by substantially increasing the number of medically relevant protein structures, as well as related reagents and protocols, available in the public domain– Human proteins (main effort)– Proteins from pathogens (e.g. Plasmodium) – Chemical probes– Biological probes

• ‘Open Source’ science– All structures/results are made freely available promptly – Funding partners receive no prior access or rights to data or

progress information– No IP

A model for open access public-private partnership

INTRODUCING THE SGCA model for open access public-private partnership

SGC University of Oxford

SGC University of Toronto

AbbvieBayer

BIGSK

JanssenLilly

MerckNovartis

PfizerTakeda

Academic Network

Wellcome Trust

Canadian Funders

SME Network

KNOWN AND EXPLORED KINASES BIOLOGYKinases: > 500,000 papers in PubMed

> 10,000 US patentsCovering mainly ~10% KinomePatents follow public data

EPIGENETICSWikipedia:

In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence.

Working Definition:Processes involved in chromatin modification transcriptional control.

Underlying Mechanism of:

Cell differentiationDisease progression

Molecular Mechanism:

Reversible DNA modificationReversible histone modificationNoncoding RNA

CREBBPEP300CLOCK

KAT2B/PCAFNCOA3NCOA1

TAF1KAT5/TIP60

KAT2A/GCN5L2MYST3MYST2MYST1TAF1L

MYST4ELP3

HAT1GTF3C4

0 100 200 300 400 500 600

Protein Acetyltransferases (18)

MLLPRMT1CARM1

NSD1WHSC1

SETD8EHMT1/GLP

PRMT3SMYD3SETD2

SMYD1SUV420H2

PRDM9PRDM15

SMYD2PRDM10

SETD1BPRDM13

SETD3Q6ZW69

0 50 100 150 200 250 300

147

1013161922252831343740

0 100 200 300 400 500 600

13579

1113151719212325

0 20 40 60 80 100 120 140 160 180 200

Bromodomains (61)

Protein demethylases (30) Protein Methyltransferases (60)

Epigenetics – here we go again………….

1950-1995

0

1000

2000

3000

4000

5000

6000

7000

Number of

Papers

Nuclear Hormone Receptors

CHEMICAL PROBES HAVE BIG IMPACT

“Open access chemical and clinical probes to support drug discovery”Nat. Chem. Bio. 2009, 5 (7), 436-440

1950-19952009

0

1000

2000

3000

4000

5000

6000

7000

* *

* ** * * *

*Chemical ProbeNumber of

Papers

Nuclear Hormone Receptors

CHEMICAL PROBES HAVE BIG IMPACT

“Open access chemical and clinical probes to support drug discovery”Nat. Chem. Bio. 2009, 5 (7), 436-440

Hit ID HitOptimization

ProbeCharacterisation

Probe Datasheet

Suppliers’Catalogues

Publications

Focused setsVLSFragmentsHTS

Analogue purchaseSynthesisSAR generationSAR analysisComplex structuresSelectivity

Secondary assaysCellular assaysSelectivity

PurifiedProtein

& Structure

Scientific Community

Epigenetics Biology

Validate Drug Targets

Assay develop-ment

Chemical Probe Criteria

• In vitro activity: IC50 or Kd 100nM• Cellular activity: IC50 1 uM• In vitro selectivity: 30-fold vs. other branches of phylogenetic tree

SGC CHEMICAL PROBE DISCOVERY

Precompetitive Space

10 big pharmas working together to make different epigenetic chemical probes

Drug Target Discovery

SGC Oxford 2015-2020

34 TEPs for novel proteins

3 targets for lead optimisation 15 novel chemical probes

VALIDATED TARGETS FOR DRU

G DISCOVERY

validation in vivo

validation in cell

in vivo probes & assays

proteins,structures,antibodies

biophysical/ biochemical

assayschemical

hits probesgene

ARUK ODDI

IMI ULTRA-DD

Wellcome TrustTEPs

Inflammation

Dementia

Metabolic

Neuro-psychiatry

Cancer

Most novel targets fail in first patient study

What is worse than spending $1.4 B on a failed experiment?

Most novel targets fail in first patient study$ 1.4 B

+ $ 1.4 B+ $ 1.4 B+ $ 1.4 B+ $ 1.4 B+ $ 1.4 B+ $ 1.4 B+ $ 1.4 B+ $ 1.4 B+ $ 1.4 B

$ 14 B

Doing it 10 times.

Most companies have patents for TRPV1

29 organizations1 mechanism

Drug Target Discovery

1. Models 2. Patients

Precompetitive Space?

Drug Target Discovery

6 big pharmas working together to make different epigenetic chemical probes.

Arch2POCM: Academics, regulators, citizens, health industry, through to Proof of Clinical Mechanism.

Would you rather spend $14,000,000,000 testing 1 target or 10 targets?

Find fit for purpose molecules to test novel mechanisms in patients.

Share all results immediately.

No IP. Freely provide all reagents.

Arch2POCM• PPP: clinically validate targets in patients

• Academics, regulators, citizens, health industry, through to Proof Of Clinical Mechanism (Phase IIa)

• Knowledge creation endeavour

• All reagents will be freely shared

“…researchers from the Institute of Cancer Research (ICR), Newcastle University and the Oxford SGC, with additional funding from Cancer Research UK and the Avon Foundation, are currently optimizing small-molecule hits that bind KDM4B, a histone demethylase enzyme recently implicated in various types of cancer.”

KDM4B in Cancer• KDM4B regulates proliferation in ER-positive breast

cancer (Kawazu et al., 2011; Shi et al., 2011)

• KDM4B is overexpressed in gastric cancer and is required for tumour cell proliferation and survival

(Li et al., 2011; Kim et al., 2012)

• KDM4B is required for colorectal cancer cell proliferation and invasion (Fu et al., 2012; Berry et al., 2014)

• KDM4B plays a role in androgen receptor signalling in prostate cancer cells (Coffey et al., 2013)

• KDM4B silencing induces DNA damage response in colorectal cancer (Chen et al., 2014)

Kawazu et al., 2011

Zoe Walters (ICR)

What happens after POCM?

Develop molecule*

Non developable

molecule

Developablemolecule

Developproprietary molecules

Developproprietarymolecules

Invalidmechanism

Publishquickly

Proceeds toindependent

fund

Valid mechanism

POCM Auction IND

66%

33%30%

70%

*Based on existing market exclusivity laws