Chemmedchem 2011-12-09

Identification of inhibitors of the Leishmania cdc2-related protein kinase CRK3.

Laura A T Cleghorn, Andrew Woodland, Iain T Collie, Leah S Torrie, Neil Norcross, Torsten Luksch, Chido Mpamhanga, Roderick G Walker, Jeremy C Mottram, Ruth Brenk, Julie A Frearson, Ian H Gilbert, Paul G Wyatt

Index: ChemMedChem 12th ed., 6 , 2214-2224, (2011)

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Abstract

New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of ~3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3-cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3-CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2.Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.