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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.
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)