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

Lig

an

ds/

com

pou

nd

s

HTS ProfilingPublic dataCommercialCustom

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. Nature Biotechnology  23, 329 - 336

(2005)

Sequence, structure, function

Human Cyclin-Dependent Kinase 2

ATP bindingsite

Leu34

PSTAIRE motif

Catalytic site

DFG motif

Human Cyclin-Dependent Kinase 2CDK2 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

Copyright ©2005 by the National Academy of Sciences

Carter, Todd A. et al. (2005) Proc. Natl. Acad. Sci. USA 102, 11011-11016

Kinase interaction maps BMS-354825 and VX-680

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 inhibitorsFrom Fabian et al. Nature Biotechnology  23, 329 (2005)