Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 6, Pages 1626-1639Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm1011726
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Funding
- NHS
- Cancer Research UK [C309/A8274, C24461/A10285]
- Royal Society
- ICR
- Cancer Research UK [11566] Funding Source: researchfish
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We describe herein the structure-activity relationship (SAR) and cocrystal structures of a series of Nek2 inhibitors derived from the published polo-like kinase 1 (Plk1) inhibitor (R)-1. Our studies reveal a nonlinear SAR for Nek2 and our cocrystal structures show that compounds in this series bind to a DFG-out conformation of Nek2 without extending into the enlarged back pocket commonly found in this conformation. These observations were further investigated, and structure-based design led to Nek2 inhibitors derived from (R)-1 with more than a hundred-fold selectivity against Plk1.
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