1. Phylogeny in Drug Discovery?

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

3. 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)

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

5. The protein kinase complement of the human genome
Manning et al. Science (2002)

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

7. Sequence, structure, function

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

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

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

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

12. Activity/selectivity of top-20 kinase compounds

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

15. Chemogenomics of kinases
Back-up

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

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

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