Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2
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- 作者：Stephen Hilton ; Sebastien Naud ; John J. Caldwell ; Kathy Boxall ; Samantha Burns ; Victoria E. Anderson ; Laurent Antoni ; Charlotte E. Allen ; Laurence H. Pearl ; Antony W. Oliver ; G. Wynne Aherne ; Michelle
- 关键词：CHK2 ; Kinase inhibitor ; High-throughput screening ; Crystallography
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2010
- 出版时间：15 January 2010
- 年：2010
- 卷：18
- 期：2
- 页码：707-718
- 全文大小：2102 K
文摘
5-(Hetero)aryl-3-(4-carboxamidophenyl)-2-aminopyridine inhibitors of CHK2 were identified from high throughput screening of a kinase-focussed compound library. Rapid exploration of the hits through straightforward chemistry established structure–activity relationships and a proposed ATP-competitive binding mode which was verified by X-ray crystallography of several analogues bound to CHK2. Variation of the 5-(hetero)aryl substituent identified bicyclic dioxolane and dioxane groups which improved the affinity and the selectivity of the compounds for CHK2 versus CHK1. The 3-(4-carboxamidophenyl) substituent could be successfully replaced by acyclic ω-aminoalkylamides, which made additional polar interactions within the binding site and led to more potent inhibitors of CHK2. Compounds from this series showed activity in cell-based mechanistic assays for inhibition of CHK2.