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

DOI: 10.1016/j.bmc.2009.11.058 DOI Help
PMID: 20022510 PMID Help

Authors: Stephen Hilton (Institute of Cancer Research) , Sebastien Naud (Institute of Cancer Research) , John J. Caldwell (Institute of Cancer Research) , Kathy Boxall (Institute of Cancer Research) , Samantha Burns (Institute of Cancer Research) , Victoria E. Anderson (Institute of Cancer Research) , Laurent Antoni (Institute of Cancer Research) , Charlotte E. Allen (Institute of Cancer Research) , Laurence H. Pearl (Institute of Cancer Research) , Antony W. Oliver (Cancer Research UK DNA Repair Enzyme Group) , G. Wynne Aherne (Institute of Cancer Research) , Michelle D. Garrett (Institute of Cancer Research) , Ian Collins (Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry , VOL 18 (2) , PAGES 707-718

State: Published (Approved)
Published: January 2010

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. (C) 2009 Elsevier Ltd. All rights reserved.

Journal Keywords: Binding; Cell; Checkpoint; Crystallography; X-Ray; Humans; Models; Molecular; Protein; Protein-Serine-Threonine; Stereoisomerism; Structure-Activity Relationship

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography