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

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Hilton S,Naud S,Caldwell JJ,Boxall K,Burns S,Anderson VE,Antoni L,Allen CE,Pearl LH,Oliver AW,Wynne Aherne G,Garrett MD,Collins I

doi

10.1016/j.bmc.2009.11.058

subject

Has Abstract

pub_date

2010-01-15 00:00:00

pages

707-18

issue

2

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(09)01076-1

journal_volume

18

pub_type

杂志文章

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