Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2

Hilton, Stephen, Naud, Sebastien, Caldwell, John J, Boxall, Kathy, Burns, Samantha, Anderson, Victoria E, Antoni, Laurent, Allen, Charlotte E, Pearl, Laurence H, Oliver, Antony W, Aherne, G Wynne, Garrett, Michelle D and Collins, Ian (2010) Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2. Bioorganic & Medicinal Chemistry, 18 (2). pp. 707-718. ISSN 0968-0896

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Abstract

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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: EPrints Services
Date Deposited: 06 Feb 2012 18:21
Last Modified: 11 Jun 2012 10:48
URI: http://sro.sussex.ac.uk/id/eprint/15889
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