Title of article :
1H-Pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases: highly potent 2,6-Difluorophenacyl analogues
Author/Authors :
Raj N. Misra، نويسنده , , Hai-yun Xiao، نويسنده , , David B. Rawlins، نويسنده , , Weifang Shan، نويسنده , , Kristen A. Kellar، نويسنده , , Janet G. Mulheron، نويسنده , , John S. Sack، نويسنده , , John S. Tokarski، نويسنده , , S. David Kimball، نويسنده , , Kevin R. Webster، نويسنده ,
Abstract :
Structure–activity studies of 1H-pyrazolo[3,4-b]pyridine 1 have resulted in the discovery of potent CDK1/CDK2 selective inhibitor 21h, BMS-265246 (CDK1/cycB IC50=6 nM, CDK2/cycE IC50=9 nM). The 2,6-difluorophenyl substitution was critical for potent inhibitory activity. A solid state structure of 21j, a close di-fluoro analogue, bound to CDK2 shows the inhibitor resides coincident with the ATP purine binding site and forms important H-bonds with Leu83 on the protein backbone.
