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

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.

SUBMITTER: Cleghorn LA

PROVIDER: S-EPMC3272345 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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

Cleghorn Laura A T LA Woodland Andrew A Collie Iain T IT Torrie Leah S LS Norcross Neil N Luksch Torsten T Mpamhanga Chido C Walker Roderick G RG Mottram Jeremy C JC Brenk Ruth R Frearson Julie A JA Gilbert Ian H IH Wyatt Paul G PG

ChemMedChem 20110913 12

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. T ...[more]

PMID: 21913331

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