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

Hilton, Stephen and Naud, Sebastien and Caldwell, John J. and Boxall, Kathy and Burns, Samantha and Anderson, Victoria E. and Antoni, Laurent and Allen, Charlotte E. and Pearl, Laurence H. and Oliver, Antony W. and Wynne Aherne, G. and Garrett, Michelle D. and Collins, Ian (2009) Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2. Bioorganic & Medicinal Chemistry, 18 (2). pp. 707-718. ISSN 0968-0896. (doi:https://doi.org/10.1016/j.bmc.2009.11.058) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://doi.org/10.1016/j.bmc.2009.11.058

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 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.

Item Type: Article
Uncontrolled keywords: CHK2; Kinase inhibitor; High-throughput screening; Crystallography
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Michelle Garrett
Date Deposited: 11 Nov 2016 11:32 UTC
Last Modified: 14 Nov 2016 16:55 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/58576 (The current URI for this page, for reference purposes)
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