1. Academic Validation
  2. 1H-Pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases: highly potent 2,6-Difluorophenacyl analogues

1H-Pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases: highly potent 2,6-Difluorophenacyl analogues

  • Bioorg Med Chem Lett. 2003 Jul 21;13(14):2405-8. doi: 10.1016/s0960-894x(03)00381-0.
Raj N Misra 1 Hai yun Xiao David B Rawlins Weifang Shan Kristen A Kellar Janet G Mulheron John S Sack John S Tokarski S David Kimball Kevin R Webster
Affiliations

Affiliation

  • 1 Bristol-Myers Squibb Pharmaceutical Research Institute, 08543-4000, Princeton, NJ, USA. [email protected]
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 IC(50)=6 nM, CDK2/cycE IC(50)=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.

Figures
Products