| Literature DB >> 16978863 |
Mark E Fraley1, Justin T Steen, Edward J Brnardic, Kenneth L Arrington, Keith L Spencer, Barbara A Hanney, Yuntae Kim, George D Hartman, Steven M Stirdivant, Bob A Drakas, Keith Rickert, Eileen S Walsh, Kelly Hamilton, Carolyn A Buser, James Hardwick, Weikang Tao, Stephen C Beck, Xianzhi Mao, Robert B Lobell, Laura Sepp-Lorenzino, Youwei Yan, Mari Ikuta, Sanjeev K Munshi, Lawrence C Kuo, Constantine Kreatsoulas.
Abstract
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 IC(50)=0.30nM) 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.Entities:
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Year: 2006 PMID： 16978863 DOI： 10.1016/j.bmcl.2006.08.118
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823