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

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Misra RN, Xiao Hy, Rawlins DB, Shan W, Kellar KA, Mulheron JG, Sack JS, Tokarski JS, Kimball SD, Webster KR

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.

PubMed ID
12824044 [ View in PubMed
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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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AlvocidibCyclin-dependent kinase 1IC 50 (nM)30830Details
AlvocidibCyclin-dependent kinase 2IC 50 (nM)170830Details
AlvocidibCyclin-dependent kinase 4IC 50 (nM)100830Details