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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 |
| Affiliation: | 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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