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Development of thioquinazolinones,allosteric Chk1 kinase inhibitors |
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| Authors: | 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 Hamilton Carolyn A Buser Xianzhi Mao Marc T Abrams Stephen C Beck Weikang Tao Rob Lobell Laura Sepp-Lorenzino Joan Zugay-Murphy George D Hartman |
| Institution: | 1. Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., P.O. Box 4, West Point, PA 19486, USA;2. Department of Cancer Research, Merck Research Laboratories, Merck & Co., P.O. Box 4, West Point, PA 19486, USA;3. Department of Structural Biology, Merck Research Laboratories, Merck & Co., P.O. Box 4, West Point, PA 19486, USA;4. Department of Automated Biotechnology, Merck Research Laboratories, Merck & Co., P.O. Box 4, West Point, PA 19486, USA |
| Abstract: | 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 Km 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. |
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