Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors
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- 作者：Shaei Huang ; Robert M. Garbaccio ; Mark E. Fraley ; Justin Steen ; Constantine Kreatsoulas ; George Hartman ; Steve Stirdivant ; Bob Drakas ; Keith Rickert ; Eileen Walsh et al.
- 关键词：Chek1 ; Kinase ; Quinolinone ; PSA ; Anticancer ; Chek1 inhibitor ; p53 ; Chekpoint escape ; Pharmacokinetics ; Indolylquinolinone
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2006
- 出版时间：15 November 2006
- 年：2006
- 卷：16
- 期：22
- 页码：5907-5912
- 全文大小：376 K
文摘
Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.