Kinases as Druggable Targets in Trypanosomatid Protozoan Parasites

Tools and approaches for understanding the essentiality of kinase targets in Trypanosoma brucei that causes HAT, T. cruzi that causes Chagas disease, and Leishmania spp. that cause the various types of leishmaniasis are reviewed. Parasite kinase inhibitor discovery has employed two complementary approaches, target-based, which focuses on selective inhibition of specific essential parasite kinases, and phenotype-based, which focuses on inhibition of cellular growth or other observable phenotypes that result from treatment with an investigational agent. Combined target and cell-based approaches during drug optimization are useful for avoiding the apparent loss of potency that is typical when a compound's activity is compared between biochemical and cellular assays. This can reflect characteristics of cellular permeability, competition with the inhibitor by cellular molecules such as ATP, and/or compensation by targets or pathways. Thus, driving medicinal chemistry optimization in a cellular assay factors in cellular permeability and provides a physiologically relevant system for testing the inhibitor.