Phylogeny in Drug Discovery?

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Presentation transcript:

Phylogeny in Drug Discovery?

Phylogeny in Drug Discovery? La place de la phylogénie en industrie pharmaceutique

Protein kinases Regulation: activation - deactivation, cell cycle, metabolisms, gene transcription, receptor signalling… Disease: cancer, diabetes, Alzheimer, obesity… Drugs: Gleevec, Iresa, Herceptin, Avastin, Tarceva, Ventolin, Rapamune Gleevec: Abelson leukemia virus tyrosine kinase, Iressa: epidermal growth factor, Avastin: Vascular Endothelial Growth Factor (VEGF)

Structure – Activity Relationship Matrix Targets/sequences Ligands/compounds HTS Profiling Public data Commercial Custom QC

The protein kinase complement of the human genome Manning et al. Science (2002) 298 1912-34

Panel of binding assays for 113 different protein kinases Panel of binding assays for 113 different protein kinases. Nature Biotechnology 23, 329 - 336 (2005)

Sequence, structure, function

DFG motif ATP binding site Leu34 Catalytic site PSTAIRE motif Human Cyclin-Dependent Kinase 2

Human Cyclin-Dependent Kinase 2 CDK2 ATP-binding pocket highlited in gray

Correlating biological activity and sequence variation Full sequence Principal component analysis According to Vieth et al. BBA 2004, 1697(1-2):243-57

Kinase interaction maps BMS-354825 and VX-680 Carter, Todd A. et al. (2005) Proc. Natl. Acad. Sci. USA 102, 11011-11016 Copyright ©2005 by the National Academy of Sciences

Activity/selectivity of top-20 kinase compounds

Phylogeny based SAR predictions Is clusterring according to chemical and biological (phylogenic) similarity possible?

Chemogenomics of kinases Back-up

Homology based SAR predictions Targets can be clustered from the SAR Data

Homology based SAR predictions Sequence Clustering Can be done using Key positions

Small molecule protein kinase inhibitors From Fabian et al. Nature Biotechnology 23, 329 (2005)