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 o...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2003-07, Vol.13 (14), p.2405-2408
Hauptverfasser: MISRA, Raj N, XIAO, Hai-Yun, RAWLINS, David B, WEIFANG SHAN, KELLAR, Kristen A, MULHERON, Janet G, SACK, John S, TOKARSKI, John S, KIMBALL, S. David, WEBSTER, Kevin R
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Sprache:eng
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Zusammenfassung: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(03)00381-0