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BIBTEX RIS

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

2003; Elsevier BV; Volume: 13; Issue: 14 Linguagem: Inglês

10.1016/s0960-894x(03)00381-0

ISSN

1464-3405

Autores

Raj N. Misra, Hai-yun Xiao, David B. Rawlins, Weifang Shan, Kristen A. Kellar, Janet G. Mulheron, John S. Sack, John S. Tokarski, S. David Kimball, Kevin R. Webster,

Tópico(s)

Advanced Breast Cancer Therapies

Resumo

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.

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