1H-Pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases: highly potent 2,6-Difluorophenacyl analogues.
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.
Misra
Raj N
RN
Bristol-Myers Squibb Pharmaceutical Research Institute, 08543-4000, Princeton, NJ, USA. raj_n_misra@hotmail.com
Xiao
Hai yun
Hy
Rawlins
David B
DB
Shan
Weifang
W
Kellar
Kristen A
KA
Mulheron
Janet G
JG
Sack
John S
JS
Tokarski
John S
JS
Kimball
S David
SD
Webster
Kevin R
KR
D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D007930:Leucine / Q000737:chemistry; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011720:Pyrazoles; D011725:Pyridines; D000255:Adenosine Triphosphate; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D007930:Leucine