硫代喹唑啉酮类变构Chk1激酶抑制剂的研发
Development of thioquinazolinones, allosteric Chk1 kinase inhibitors.
作者信息
Converso Antonella, Hartingh Timothy, Garbaccio Robert M, Tasber Edward, Rickert Keith, Fraley Mark E, Yan Youwei, Kreatsoulas Constantine, Stirdivant Steve, Drakas Bob, Walsh Eileen S, Hamilton Kelly, Buser Carolyn A, Mao Xianzhi, Abrams Marc T, Beck Stephen C, Tao Weikang, Lobell Rob, Sepp-Lorenzino Laura, Zugay-Murphy Joan, Sardana Vinod, Munshi Sanjeev K, Jezequel-Sur Sylvie Marie, Zuck Paul D, Hartman George D
机构信息
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486, USA.
出版信息
Bioorg Med Chem Lett. 2009 Feb 15;19(4):1240-4. doi: 10.1016/j.bmcl.2008.12.076. Epub 2008 Dec 24.
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 approximately 13A from the ATP binding site. Preliminary data is presented for several of these compounds.
设计了一项高通量筛选活动，通过在高浓度下测试化合物来鉴定Chk1激酶的变构抑制剂。然后在ATP的米氏常数（K(m)）以及接近生理浓度的ATP条件下观察活性。该策略导致发现了一个非ATP竞争性的硫代喹唑啉酮系列，该系列针对效力和稳定性进行了优化。解析了我们最佳抑制剂与Chk1结合复合物的X射线晶体结构，表明它结合在距ATP结合位点约13埃的变构位点上。给出了其中几种化合物的初步数据。
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