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Drug Targets - an overview of historical success and protein kinase inhibitors - successes and attrition John P. Overington [email protected] 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 Compound Assay/Target Ki = 4.5nM Bioactivity data ED2 = 230 nM 2. Organization, curation and standardization of structure and pharmacology data ChEMBL https://www.ebi.ac.uk/chembl • The world’s largest primary public database of medicinal chemistry data • ~1.4 million compounds • ~9,000 targets • ~12 million bioactivities – 11 years (2008-2019) funding from Wellcome Trust – Open license – Downloadable – Regular updates A. Gaulton et al (2012) Nucleic Acids Research Database Issue. 40 D1100-1107 SureChEMBL http://www.surechembl.org • 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 1.6% of Human Genome is a Drug Target 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Monoclonal antibody Other protein Polymer Peptide Oligonucleotide Oligosaccharide Inorganic Other Other Santos et al, unpublished Drug Efficacy Targets and Drugs Santos et al, unpublished Innovation in Drug Approvals Privileged Target Families ChEMBL17 Santos, unpublished Approved Drugs Privileged Target Families Over 53% of all drug efficacy targets are from four target families (70% of drugs) Rhodopsin-like GPCR PDBe: 3sn6 Ion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 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 Protein kinases PDBe: 4foc 13% of drug targets 2.4% of small mol drugs The Clinical Kinome • 455 Clinical stage human kinase inhibitors • 31 Approved small molecule kinase inhibitors • 43 Phase 3 • 150 Phase 2 • 231 Phase 1 Overington, Bellis, Al-Lazikani & Wennerberg, unpublished Kinase Inhibitor Attrition Overington, unpublished Kinase Inhibitor Attrition USAN assignment to approved fraction – ~0.2 is long term mean for all drugs across all classes Overington, unpublished Kinase Inhibitor Productivity Overington, unpublished Drug Trials Randomized Clinical Trial Mendelian Randomization Drug perturbation of ‘disease’ gene function Genetic perturbation of ‘disease’ gene function Drug dosing at start of treatment Random assignment of drug target gene allele at birth Drug No Drug Differential health outcomes/b iomarkers Hingorani & Casas (UCL) aa allele ab allele bb allele 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 – 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) • Hingorani & Casas (UCL) UCL BRC High Impact funding for drug target genotyping – Chip design and genotyping costs – Phenotyping of genotyped patients