Authors
M Saldivia1; J Jiricek1; S Rao1; 1 Novartis Institute for Tropical Diseases, United States Discussion
The current therapeutic challenges for kinetoplastid neglected tropical diseases (NTDs) ranges from toxicity, poor efficacy, difficult administration, or prohibitive cost. From a phenotypic screening, we recently identified AB1, an Amidobenzimidazole compound active across various kinetoplastids parasites. Detailed target deconvolution studies using Trypanosoma brucei revealed CLK1 as AB1 primary target. Further optimization of AB1 through medicinal chemistry efforts resulted in the AB3, a novel compound with improved potency against not only T. brucei but also Trypanosoma cruzi. AB3 compound showed promising inhibitory activity against the Trypanosoma CLK1 enzyme with improved selectivity against host kinases. Incubation of AB3 compound with parasite resulted in cell cycle progression defects. AB3 had favorable pharmacokinetic properties, which led to an evaluation in mice models of sleeping sickness and Chagas disease. Treatment with AB3 resulted in the complete cure of mice in the hemolymphatic model of sleeping sickness at significantly lower doses than AB1. AB3 also showed partial cure in the mice model of Chagas disease after three rounds of immunosuppression. Together with in vitro CLK1 inhibition and the mitosis defects, our studies indicate that Trypanosoma cidality after treatment could result from inhibition of CLK1 kinase activity and triggers a new treatment venue for these diseases. 
