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., and others. (2009) Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2. Bioorganic & Medicinal Chemistry, 18 (2). pp. 707-718. ISSN 0968-0896. (doi: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) (KAR id:58576)

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.
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 ?-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
DOI/Identification number:	10.1016/j.bmc.2009.11.058
Uncontrolled keywords:	CHK2; Kinase inhibitor; High-throughput screening; Crystallography
Subjects:	Q Science
Divisions:	Divisions > Division of Natural Sciences > Biosciences
Depositing User:	Michelle Garrett
Date Deposited:	11 Nov 2016 11:32 UTC
Last Modified:	05 Nov 2024 10:49 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/58576 (The current URI for this page, for reference purposes)

University of Kent Author Information

Garrett, Michelle D..

Creator's ORCID:	https://orcid.org/0000-0002-3939-1673
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