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SGC OxfordSGC TorontoSGC Stockholm Chas Bountra University of Oxford Proteins, Structures, Chemical probes and Target Discovery – all Open Access.

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Presentation on theme: "SGC OxfordSGC TorontoSGC Stockholm Chas Bountra University of Oxford Proteins, Structures, Chemical probes and Target Discovery – all Open Access."— Presentation transcript:

1 SGC OxfordSGC TorontoSGC Stockholm Chas Bountra University of Oxford Proteins, Structures, Chemical probes and Target Discovery – all Open Access.

2 Outline Public Private Partnership (PPP): - pool resources - share risk No IP: - facilitate collaboration - access best labs quickly and freely Disseminate data quickly: - reduce wastage of resource - potentially reduce unnecessary patient exposure Gene sequence, protein structures, chemical probes……validation of novel targets in patients – “proof of clinical mechanism” (POCM) Epigenetic proteins are better targets for Drug Discovery

3 SGC: Structural Genomics Consortium Established 7 years ago Based in Univ. of Toronto, Karolinska Institutet and Univ. of Oxford 200 scientists Funded by - private: GSK, Merck, Novartis - govt: Canada, Sweden - charities: Wellcome Trust, Wallenberg Foundation

4 Objective Human protein structures - therapeutically relevant targets - selected by funders

5 Achievements More than 1000 human protein structures (nearly 25% of PDB) Have purified 2000 human proteins >1 publication per week (11 in past two years in Science, Cell, Nature) 500 cDNA clones distributed freely every year (academia, biotech, pharma)

6 Our modus operandi Do, and enable great science Work with the very best (250+ collaborations) Disseminate data immediately Publish in high impact journals Exceed objectives agreed with funders No IP

7 Impact of “no IP” Collaborate quickly with any scientist, lab or institution Work closely with multiple private organisations, on same project Generate data quickly Place data in public domain quickly

8 50% of all human protein kinase structures solved by SGC (in past 5 years)

9 22 novel structures in one paper 23/ 34 Human Phosphatase structures solved by SGC Compare binding sites - predict off target activity Design allosteric inhibs Proteins for - screening and chemical probe ID - antibody production

10 Jan 09 Well. Trust (£4.1M) NCGC (20HTSs) GSK (8FTEs) Ontario ($5.0M) OICR (2FTEs) UNC (3FTEs) April 09 June 09 June 10 Pfizer (8FTEs) Novartis (8FTEs) Epigenetics Chemical Probes Consortium Sweden ($3.0M) 15 acad. labs ….more than £30M of resource….now Lilly (8FTEs)

11 Why epigenetics? Potential in many therapeutic areas: oncology, neuro-psychiatric, inflammation, metabolic…. Underestimated role of environment, stress, diet, injury, chronic drug use, early life experiences… Early in cascade, not single late stage mediator

12 Peripheral nerve injury (PNI) Increase Neurone Restrictive Silencer Factor (NRSF) in DRG Bind to Neurone Restrictive Silencer Element (NRSE) Decreased histone acetylation Decreased transcription of mu opioid receptor, Nav1.8, Kv4.3 PNI induced epigenetic gene silencing Uchida et al 2010, J of Neuroscience, Uchida et al 2010, Neuroscience

13 Uchida et al 2010, J of Neuroscience Decreased acetylation of mu opioid receptor through NRSF binding

14 HDACi are anti-hyperalgesic HDACi Increased acetylation of p65RelA Increased mGluR2 expression Decreased neurotransmitter release from primary afferents Anti-hyperalgesia Chiechio et al 09

15 HDACi increases expression of mGluR2 in lumbar cord (not 1a, 5 and 4) MS275 (HDAC inhib): 5 days, 3mg/kg sc Chiechio et al 09

16 Maternal care, increases GR expression and dampens stress response Maternal care increases TF NGFI-A and histone acetylation, decreases DNA methylation and increases GR expression Methionine promotes methylation and Low LG phenotype HDAC inhibs increase acetylation and High LG phenotype McGowan et al 08 TSA – Trichostatin A (HDAC inhib), SAM – S adenosyl methionine

17 Childhood abuse decreases glucocorticoid receptor Post mortem hippocampus Decreased GR, leads to increased stress response Also decreased NGFI-A McGowan et al 09

18 Childhood abuse increases methylation of glucocorticoid receptor McGowan et al 09

19 Covington et al 2009 HDAC inhibs have anti-depressant like effects After 10 days chronic social defeat stress Infused MS275 or SAHA 100μM

20 Covington et al 2009 Social defeat stress induced changes in gene expression are partially reversed by MS275 or fluoxetine MS275: 100μM infusion into NAc Fluoxetine: 20mg/kg/day For 10 days after chronic (10days) social defeat stress

21 T cell differentiation is associated with modifications of signature cytokines H3K4me3 - activating H3K27me3 - repressing Genome wide maps - ChIP Seq Signature cytokines as expected Wei et al 09

22 JmjD3 is increased in activated macrophages De Santa et al 07

23 Transient hyperglycemia produces long lasting changes in human AECs Transient hyperglycemia in HAECs Increased reactive oxygen species Increase in SET7 Increase in H3K4me1 Increase in NFKβp65 Increase in MCP1 and VCAM1 El-Osta 2008

24 Transient hyperglycemia produces sustained elevation of SET7 binding and H3K4me1 El-Osta 2008

25 Modulating a late stage mediator is unlikely to be effective BirthDeath Trauma - tissue damage/ nerve injury/ surgery - infection - stress/ abuse - ischemia - toxins - drugs Nos of genes/ proteins, up/down regulated

26 Bromodomain proteins recognise KAc on histone tails

27 31 Bromodomain structures

28 <100 nM >30-fold selectivity vs other sub-families Cellular potency <1µM Bromodomain Probes - Target Profile

29 A pre-probe shows sub-family selectivity

30 BRD4 pre probe shows enantiomeric specificity

31 JQ1 reduces proliferation in two patient derived cell lines KI67 positive = proliferating

32 JQ1 induces apoptosis Annexin V, marker of early apoptosis PI = propidium iodide, marker of late apoptosis STA = Staurosporine

33 JQ1 inhibits tumour growth

34 Speed, cost and impact of probe 2 months: from molecule to submission of publication No cost to us: much of functional data generated by collaborator at Harvard via network of labs Probe has already been sent to 250+ labs throughout the world for evaluation in multiple disease areas

35 FamilyNumber of targets Purified in SGC Assays established in SGC Structures deposited [SGC/Total] Lysine demethylase (KDM) /8 Bromodomain (BRD) /17 ROYALROYAL Tudor domain /19 Chromo domain /16 MBT domain 9834/7 PHD /23 Histone acetyltransferase (HAT) 17855/8 Histone methyltransferase (HMT) /18 TOTAL /116 Already deposited half of all structures

36 Creating reagents to accelerate and improve Target Discovery SGC Global biomedical community Structures Chemical probes Proteins 1) Reagents freely available 2) Many collaborations with clinicians and disease experts: access to assays and new technologies 3) Leveraged resource

37 Problems with way we do Drug Discovery Same targets, in parallel, in secret (duplication, wastage, patients being unnecessarily exposed) Target validation is best done in patients (preclinical assays have limited utility) No one organisation has all capabilities Early IP is making it even harder (slows collaboration, restricts competition, makes process more expensive)

38 Largest attrition for novel targets is at clinical POC Target ID/ Discovery Hit/ Probe/ Lead ID Clinical candidate ID Tox./ Pharmacy Phase I Phase IIa/ b HTS LO 10%30% 90+% 50% this is killing our industry …we can generate “safe” molecules, but they are not developable in chosen patient group

39 This failure is duplicated, many times Target ID/ Discovery Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b HTS 30% 90+% Target ID/ Discovery Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b 30% 90+% Target ID/ Discovery Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b 30% 90+% Target ID/ Discovery Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b 30% 90+% Target ID/ Discovery Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b 30% 90+% Target ID/ Discovery Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b 30% 90+% Target ID/ Discovery Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b 10%30% 90+% 50% LO …outcomes are not shared

40 TRPV1 patents by company

41 TRPV1 patents by disease – all therapeutic areas

42 Solution A Public Private Partnership to take pioneer targets through to Phase II (Proof of Clinical Mechanism) Create IP only on developable assets, after positive POCM studies Publish all negative studies immediately and positive studies after a small delay Objective is to generate pioneer, clinically validated, de- risked targets which pharma can convert into new drugs

43 Plans post POCM 1 or more partners develop probe Non developable probe Developable probe Other partners develop proprietary molecules All partners develop proprietary molecules Invalid mechanism Publish quickly Proceeds to independent research fund Valid mechanism POCM Secure IP, auction IND to partners 90% 10% 90%

44 Benefits of such a model Pool resources (charitable, govt, philanthropic, private) and share risk Access global academia quickly and freely Rapid publication reduces duplication and saves patients

45 Toronto Summit Feb 2011 Aled Edwards and Stephen Friend 5 stakeholder groups: pharma, public funders, patient groups, regulators, academics Outcomes - Patient groups will facilitate recruitment and minimise costs of trials - Regulators will help validate new clinical endpoints and develop new study designs - 41/ 43 in favour of model (2 from academic tech transfer did not vote) Recommendation: do now, not pilot

46 Shifting the pre-competitive boundary 1999human gene sequence 2003human protein structures 2009chemical probes to enable target discovery 2012novel, clinically validated targets

47 Acknowledgements SGC Stefan Knapp, Tom Heightman Aled Edwards: SGC, Toronto Stephen Friend: Sage Bionetworks, Seattle Toronto Summit attendees

48

49 Sharing costs, sharing risks and creating benefits PPP - novel targets - through POCM Academia (probes) Pharma (probes and candidates) Clinically validated targets (10%) Clinically invalidated targets (90%) National health/ clinical infrastructures - patient databases - stratified patients - biomarkers - tissue banks

50 Where will assets come from? Pharma - “ineffective but safe” clinical candidates - de-prioritised clinical probes - short or no patent compounds Academia - new clinical probes - existing drugs for new indications probe = good enough to invalidate target candidate = “potential” to be a drug

51 Target ID/ Discovery Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b HTS LO 10%30% 90+% 50% Clinical probes De-prioritised assets Focus of PPP

52 How can probe be commercially viable after a positive POCM? Following data will not be published - route for large scale synthesis - impurities - “patient drop-outs” ……

53 Since Toronto Chosen 3 therapeutic areas - Oncology - Inflammation - CNS Starting to identify leaders (academic and industrial) and academic centres (Oxford, Toronto, UCSF) Collating input of senior therapeutic heads in pharma - who are academic leaders? - which are best academic centres? - which diseases should we focus on? Defining deliverables, timelines and costs with pharma colleagues

54 Meeting planned in San Francisco April 16/17 Meeting of individuals and organisations that will operationalise Start compiling business plan Aim to start Jan 2012 Calling it ARCH2POCM - Academics, Regulators, Citizens, Health industry - virtual organisation operating as an ARCHipelago - Proof Of Clinical Mechanism


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