Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3

Article abstract of DOI:10.1002/cmdc.201100344

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-cyclin6 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. Selective at last: [1,2,4]Triazolo[1,5-a]pyridines, aminopyrazoles, and disubstituted ureas were explored as potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3-cyclin6 complex. 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.