Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2

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• 作者：John J. Caldwell ; Emma J. Welsh ; Cornelis Matijssen ; Victoria E. Anderson ; Laurent Antoni ; Kathy Boxall ; Frederique Urban ; Angela Hayes ; Florence I. Raynaud ; Laurent J. M. Rigoreau ; Tony Raynham ; G. Wynne Aherne ; Laurence H. Pearl ; Antony W. Oliver ; Michelle D. Garrett ; Ian Collins
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：January 27, 2011
• 年：2011
• 卷：54
• 期：2
• 页码：580-590
• 全文大小：1074K
• 年卷期：v.54,no.2(January 27, 2011)
• ISSN：1520-4804

文摘

Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure鈭抋ctivity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC₅₀ 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).