1H-pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases: Highly potent 2,6-difluorophenacyl analogues

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

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63 Scopus citations

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 IC50=6 nM, CDK2/cycE IC50=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.

Original languageEnglish (US)
Pages (from-to)2405-2408
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume13
Issue number14
DOIs
StatePublished - Jul 21 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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