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

Hilton, S.T., Naud, S., Caldwell, J.J., Boxall, K., Burns, S., Anderson, V.E., Antoni, L., Allen, C.E., Pearl, L.H. and Oliver, A.W. (2010) Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2. Bioorganic and Medicinal Chemistry, 18 (2). pp. 707-718. 10.1016/j.bmc.2009.11.058.

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DOI: 10.1016/j.bmc.2009.11.058


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
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry
ID Code:2061
Journal or Publication Title:Bioorganic and Medicinal Chemistry
Deposited By:Library Staff
Deposited On:06 May 2011 10:23
Last Modified:06 May 2011 10:23

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