Authors

Discussion

Protein kinases (PKs) are attractive drug targets since they play an essential role in signaling pathways for growth and differentiation and, more importantly, are amenable for inhibition by small-molecules. Protozoan PKs differ significantly from those in mammalian systems making them attractive for selective drug targeting. A focused high-throughput screening effort to identify growth inhibitors against Trypanosoma brucei using Novartis kinase inhibitor library led to identification of multiple potent hits. Further bio-centric characterization of these hits resulted in identification of non-cytotoxic, cidal chemical scaffold with favorable drug-like properties.

One of the major challenges for progressing hits to lead obtained from phenotypic screens is the identification of the target that is responsible for the phenotypic effect. We have used a T. brucei gain of function library of essential PKs to identify and validate an essential protein kinase as the target for one of these compound series. The inhibition of this PK dramatically compromises the cell cycle progression of parasites.  The PK is a component of the kinetochore and its inhibition via chemical or genetic perturbation leads to disruption of kinetochore assembly.  We have thus identified a novel mechanism of action and a novel drug target for African trypanosomes and a new chemical tool for investigation the biology of the parasite.