Drug Targets - an overview of historical success and protein kinase inhibitors - successes and attrition. John P. Overington

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1 Drug Targets - an overview of historical success and protein kinase inhibitors - successes and attrition John P. Overington jpo@ebi.ac.uk

2 Assay/Target ChEMBL The Organisation of Drug Discovery 1. Scientific facts 3. Insight, tools and resources for translational drug discovery >Thrombin MAHVRGLQLPGCLALAALCSLVHSQHVFLAPQQARSLLQRV RRANTFLEEVRKGNLERECVEETCSYEEAFEALESSTATDV FWAKYTACETARTPRDKLAACLEGNCAEGLGTNYRGHVNIT RSGIECQLWRSRYPHKPEINSTTHPGADLQENFCRNPDSST TGPWCYTTDPTVRRQECSIPVCGQDQVTVAMTPRSEGSSVN LSPPLEQCVPDRGQQYQGRLAVTTHGLPCLAWASAQAKALS KHQDFNSAVQLVENFCRNPDGDEEGVWCYVAGKPGDFGYCD LNYCEEAVEEETGDGLDEDSDRAIEGRTATSEYQTFFNPRT FGSGEADCGLRPLFEKKSLEDKTERELLESYIDGRIVEGSD AEIGMSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLY PPWDKNFTENDLLVRIGKHSRTRYERNIEKISMLEKIYIHP RYNWRENLDRDIALMKLKKPVAFSDYIHPVCLPDRETAASL LQAGYKGRVTGWGNLKETWTANVGKGQPSVLQVVNLPIVER PVCKDSTRIRITDNMFCAGYKPDEGKRGDACEGDSGGPFVM KSPFNNRWYQMGIVSWGEGCDRDGKYGFYTHVFRLKKWIQK VIDQFGE K i = 4.5nM Compound Bioactivity data ED 2 = 230 nm 2. Organization, curation and standardization of structure and pharmacology data

3 ChEMBL A. Gaulton et al (2012) Nucleic Acids Research Database Issue. 40 D The world s largest primary public database of medicinal chemistry data ~1.4 million compounds ~9,000 targets ~12 million bioactivities 11 years ( ) funding from Wellcome Trust Open license Downloadable Regular updates

4 SureChEMBL Acquired SureChem from Digital Science >15 million chemical structures Automatically extracted chemical structures from fulltext patent Overnight! Community wants open access to useable patent data Patent literature 2-3 years ahead of published literature Better competitive position Larger compound and target coverage Provide ongoing free, Open resource to entire community

5 1.6% of Human Genome is a Drug Target

6 Different Types of Drugs USANs Assigned 2013 Drugs Approved 2013 Synthetic small molecule Natural product-derived small molecule Monoclonal antibody Other protein Polymer Peptide Oligonucleotide Oligosaccharide Inorganic Other Other Santos et al, unpublished

7 Drug Efficacy Targets and Drugs Santos et al, unpublished

8 Innovation in Drug Approvals

9 Privileged Target Families ChEMBL17 Approved Drugs Santos, unpublished

10 Privileged Target Families Over 53% of all drug efficacy targets are from four target families (70% of drugs) Rhodopsin-like GPCR PDBe: 3sn6 Ion channels PDBe: 4kfm Nuclear receptors PDBe: 3e00 Protein kinases PDBe: 4foc 22% of drug targets 33% of small mol drugs 12% of drug targets 18% of small mol drugs 6% of drug targets 17% of small mol drugs 13% of drug targets 2.4% of small mol drugs

11 The Clinical Kinome 455 Clinical stage human kinase inhibitors 31 Approved small molecule kinase inhibitors 43 Phase Phase Phase 1 Overington, Bellis, Al-Lazikani & Wennerberg, unpublished

12 Overington, unpublished Kinase Inhibitor Attrition

13 Kinase Inhibitor Attrition USAN assignment to approved fraction ~0.2 is long term mean for all drugs across all classes Overington, unpublished

14 Overington, unpublished Kinase Inhibitor Productivity

15 Drug Trials Randomized Clinical Trial Drug perturbation of disease gene function Drug dosing at start of treatment Mendelian Randomization Genetic perturbation of disease gene function Random assignment of drug target gene allele at birth Drug No Drug aa allele ab allele bb allele Differential health outcomes/b iomarkers Hingorani & Casas (UCL)

16 Mendelian Randomization & Target Validation Comprehensive set of tag SNPs for all druggable targets Efficacy targets of approved drugs (small mol, mab and other protein therapeutic) drug repurposing Efficacy targets of clinical candidates target validation, drug trial support and stratification ADME associated proteins (transporters, metabolic enzymes) pharmacogenomics, safety and differential response ChEMBL targets (binding drug-like small molecules) prioritization/initiation/de-risking of discovery programs Close homologues of drug efficacy targets development of novel selective agents Hingorani & Casas (UCL) Extracellular proteins (biotherapeutics) address important future role of mabs Members of privileged target families (GPCRs, kinases, ion channels, nuclear hormone receptors, PDEs) aligned coverage to community profiling studies (e.g. NIH informing druggable genome) UCL BRC High Impact funding for drug target genotyping Chip design and genotyping costs Phenotyping of genotyped patients