Cdc2-related kinase 12 (CRK12) (CRK12)

Cdc2-related kinase 12 (CRK12) is an essential cyclin-dependent kinase (CDK) in the protozoan parasite Leishmania donovani, the causative agent of visceral leishmaniasis (Nature, 2018). It functions in a complex with its cognate cyclin, CYC9, to regulate critical stages of the parasite's cell cycle, specifically the G1 and G2/M transitions (Nature, 2018; NIH). CRK12 was identified as a high-priority therapeutic target through the deconvolution of a potent anti-leishmanial pyrazolopyrimidine series, including the preclinical candidate GSK3186899, also known as DDD853651 (Nature, 2018; University of Dundee). Inhibition of CRK12 leads to irreversible cell cycle arrest and parasite death in both the promastigote and the clinically relevant intracellular amastigote stages (Nature, 2018). Because CRK12 is essential for parasite survival and possesses structural differences from human CDKs, it offers a viable window for selective toxicity (Nature, 2018; NIH). Current drug discovery efforts focus on small-molecule inhibitors that bind to the ATP-binding pocket of the enzyme to treat visceral leishmaniasis, a neglected tropical disease with limited oral treatment options (Nature, 2018; MDPI).

Other names

LdCRK12Cyclin-dependent kinase 12Cell division cycle 2-related kinase 12LdBPK_090270

Inhibition of kinase activity via ATP-competitive binding, leading to cell cycle arrest at G1 and G2/M phases and subsequent parasite death.