Pyridyl aminothiazoles as potent inhibitors of Chk1 with slow dissociation rates

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• 作者：Vadim Y. Dudkin^a ; ^{vadim_dudkin@merck.com} ; Keith Rickert^b ; Constantine Kreatsoulas^a ; Cheng Wang^a ; Kenneth L. Arrington^a ; Mark E. Fraley^a ; George D. Hartman^a ; Yowei Yan^a ; Mari Ikuta^a ; Steven M. Stirdivant^b ; Robert A. Drakas^b ; Eileen S. Walsh^b ; Kelly Hamilton^b ; Carolyn A. Buser^b ; Robert B. Lobell^b ; Laura Sepp-Lorenzino^b
• 关键词：Checkpoint kinase ; Chk1 inhibitors ; DNA damage ; Cancer therapy ; Combination cancer therapy ; Molecular dynamics ; ATP-competitive kinase inhibitors
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 April, 2012
• 卷：22
• 期：7
• 页码：2609-2612
• 文件大小：1935 K

摘要

Pyridyl aminothiazoles comprise a novel class of ATP-competitive Chk1 inhibitors with excellent inhibitory potential. Modification of the core with ethylenediamine amides provides compounds with low picomolar potency and very high residence times. Investigation of binding parameters of such compounds using X-ray crystallography and molecular dynamics simulations revealed multiple hydrogen bonds to the enzyme backbone as well as stabilization of the conserved water molecules network in the hydrophobic binding region.