Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase
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- 作者：Robert M. Garbaccio ; Shaei Huang ; Edward S. Tasber ; Mark E. Fraley ; Youwei Yan ; Sanjeev Munshi ; Mari Ikuta ; Lawrence Kuo ; Constanine Kreatsoulas ; Steve Stirdivant ; Bob Drakas ; Keith Rickert ; Eileen S.
- 关键词：Chk1 kinase ; Chek1 kinase ; Kinases ; Photochemistry ; Benzoisoquinolinones ; PSA ; DNA damaging agents ; Mitotic arrest ; Checkpoint escape ; p53-Deficient cancer ; Cancer ; Apoptosis
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2007
- 出版时间：15 November 2007
- 年：2007
- 卷：17
- 期：22
- 页码：6280-6285
- 全文大小：260 K
文摘
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.