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Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase |
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| Authors: | Garbaccio Robert M Huang Shaei Tasber Edward S Fraley Mark E Yan Youwei Munshi Sanjeev Ikuta Mari Kuo Lawrence Kreatsoulas Constanine Stirdivant Steve Drakas Bob Rickert Keith Walsh Eileen S Hamilton Kelly A Buser Carolyn A Hardwick James Mao Xianzhi Beck Stephen C Abrams Marc T Tao Weikang Lobell Rob Sepp-Lorenzino Laura Hartman George D |
| Institution: | Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. robert_garbaccio@merck.com |
| Abstract: | From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1. |
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