Development of thioquinazolinones, allosteric Chk1 kinase inhibitors

被引：69

作者：

Converso, Antonella ^{[1
]}

Hartingh, Timothy ^{[1
]}

Garbaccio, Robert M. ^{[1
]}

Tasber, Edward ^{[1
]}

Rickert, Keith ^{[2
]}

Fraley, Mark E. ^{[1
]}

Yan, Youwei ^{[3
]}

Kreatsoulas, Constantine ^{[1
]}

Stirdivant, Steve ^{[2
]}

Drakas, Bob ^{[2
]}

Walsh, Eileen S. ^{[2
]}

Hamilton, Kelly ^{[2
]}

Buser, Carolyn A. ^{[2
]}

Mao, Xianzhi ^{[2
]}

Abrams, Marc T. ^{[2
]}

Beck, Stephen C. ^{[2
]}

Tao, Weikang ^{[2
]}

Lobell, Rob ^{[2
]}

Sepp-Lorenzino, Laura ^{[2
]}

Zugay-Murphy, Joan ^{[3
]}

Sardana, Vinod ^{[3
]}

Munshi, Sanjeev K. ^{[3
]}

Jezequel-Sur, Sylvie Marie ^{[4
]}

Zuck, Paul D. ^{[4
]}

Hartman, George D. ^{[1
]}

机构：

[1] Merck & Co Inc, Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck & Co Inc, Merck Res Labs, Dept Canc Res, West Point, PA 19486 USA

[3] Merck & Co Inc, Merck Res Labs, Dept Biol Struct, West Point, PA 19486 USA

[4] Merck & Co Inc, Merck Res Labs, Dept Automated Biotechnol, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 04期

关键词：

Chk1; Thioquinazolinone; Allosteric kinase inhibitor; X-ray crystal structure; CELLS; DOMAIN;

D O I：

10.1016/j.bmcl.2008.12.076

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 similar to 13 angstrom from the ATP binding site. Preliminary data is presented for several of these compounds. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：1240 / 1244

页数：5

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