title: 1H-Pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases: highly potent 2,6-Difluorophenacyl analogues.
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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, 08543-4000, Princeton, NJ, USA. raj_n_misra@hotmail.com
authors.forename: Raj N
authors.initials: RN
authors.lastname: Misra
authors.forename: Hai yun
authors.initials: Hy
authors.lastname: Xiao
authors.forename: David B
authors.initials: DB
authors.lastname: Rawlins
authors.forename: Weifang
authors.initials: W
authors.lastname: Shan
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Kellar
authors.forename: Janet G
authors.initials: JG
authors.lastname: Mulheron
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: S David
authors.initials: SD
authors.lastname: Kimball
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Webster
mesh_terms: 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
chemical_list: 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