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Bioorg Med Chem. 2010 Jan 15;18(2):707-18. doi: 10.1016/j.bmc.2009.11.058. Epub 2009 Dec 6.

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

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1
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.

Erratum in

  • Bioorg Med Chem. 2010 Jun 15;18(12):4591.

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.

PMID:
20022510
DOI:
10.1016/j.bmc.2009.11.058
[Indexed for MEDLINE]

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