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<title>Author Summary</title> <p>CRK3, a cdc2-related serine/threonine protein kinase of the CDK family, is essential for transition through the G2-M phase checkpoint of the <italic>Leishmania</italic> cell cycle. An expression and purification system has been developed to produce active <italic>L. major</italic> CRK3 in complex with a cyclin partner, CYC6. CRK3:CYC6 was used to develop an assay suitable for high throughput screening (HTS) using IMAP fluorescence polarization technology. Two compound chemical libraries were screened against CRK3:CYC6 and counter screened against a human cyclin-dependent kinase complex CDK2:CycA. Two main chemical families of inhibitors were identified that specifically inhibited the leishmanial cyclin-dependent kinase, the azapurines and the thiazoles. Structure activity relationship (SAR) analysis of the hits identified the chemical groups attached to the azapurine scaffold that are essential for the inhibition of CRK3:CYC6 protein kinase activity. The CRK3:CYC6 hits were subsequently tested against a panel of 11 mammalian kinases including human CDK1:CYCB, human CDK2:CYCA and human CDK4:CYCD1 to determine their selectivity. Compounds selective to CRK3:CYC6 were tested against <italic>Leishmania</italic>. Progress towards synthesising potent and selective derivatives of the HTS hits are discussed, with the view to evaluating their potential for the development of novel therapeutics against leishmaniasis.</p>

Original publication




Journal article


PLoS Negl Trop Dis


Public Library of Science




e1033 - e1033