3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6

详细信息    查看全文

• 作者：Mark E. Fraley ; Justin T. Steen ; Edward J. Brnardic ; Kenneth L. Arrington ; Keith L. Spencer ; Barbara A. Hanney ; Yuntae Kim ; George D. Hartman ; Steven M. Stirdivant ; Bob A. Drakas ; et al.
• 关键词：Chek1 kinase ; Checkpoint escape ; DNA damage ; CDK7 kinase ; Oncology ; Indazoles ; Indoles
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2006
• 出版时间：1 December 2006
• 年：2006
• 卷：16
• 期：23
• 页码：6049-6053
• 全文大小：248 K

文摘

The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC₅₀ = 0.30 nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft.