Download Drug Targets

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Santos et al, unpublished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Santos et al, unpublished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Santos, unpublished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