Development of thioquinazolinones, allosteric Chk1 kinase inhibitors

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• 作者：Antonella Converso ; Timothy Hartingh ; Robert M. Garbaccio ; Edward Tasber ; Keith Rickert ; Mark E. Fraley ; Youwei Yan ; Constantine Kreatsoulas ; Steve Stirdivant ; Bob Drakas ; Eileen S. Walsh ; Kelly Hamil
• 关键词：Chk1 ; Thioquinazolinone ; Allosteric kinase inhibitor ; X-ray crystal structure
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：15 February 2009
• 年：2009
• 卷：19
• 期：4
• 页码：1240-1244
• 全文大小：1593 K

文摘

A high throughput screening campaign was designed to identify allosteric inhibitors of Chk1 kinase by testing compounds at high concentration. Activity was then observed at K_m for ATP and at near-physiological concentrations of ATP. This strategy led to the discovery of a non-ATP competitive thioquinazolinone series which was optimized for potency and stability. An X-ray crystal structure for the complex of our best inhibitor bound to Chk1 was solved, indicating that it binds to an allosteric site 13 Å from the ATP binding site. Preliminary data is presented for several of these compounds.