Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 18, Issue 2, Pages 707-718Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.11.058
Keywords
CHK2; Kinase inhibitor; High-throughput screening; Crystallography
Funding
- Cancer Research UK [CUK] [C309/A2187, C309/A2874, C309/A8365, C302/A8265, C302/A7803]
- Institute of Cancer Research
- NHS
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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 omega-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. (C) 2009 Elsevier Ltd. All rights reserved.
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