Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 16, Issue 23, Pages 6049-6053Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2006.08.118
Keywords
Chek1 kinase; checkpoint escape; DNA damage; CDK7 kinase; oncology; indazoles; indoles
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The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC50 = 0.30 nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft. (c) 2006 Elsevier Ltd. All rights reserved.
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