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.

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.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Binding Sites / drug effects
  • CDC2-CDC28 Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / chemistry
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Hydrogen Bonding
  • Indicators and Reagents
  • Leucine / chemistry
  • Models, Molecular
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology*
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Indicators and Reagents
  • Pyrazoles
  • Pyridines
  • Adenosine Triphosphate
  • CDC2-CDC28 Kinases
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Leucine