Kinase Inhibitors Among Hits from Malaria Cellular Screens

Abstract

Tens of thousands of small molecules possessing potent inhibitory activity against Plasmodium falciparum blood stages have recently been disclosed by several groups. One of those published sets of hits has been named the Tres Cantos Antimalarial Set (TCAMS), and is composed of 13 533 individual compounds, most of them with submicromolar IC50-values against parasites growing in vitro. The molecular basis of their antimalarial action on the parasite or the infected erythrocyte is for the most part unknown. A minority of the compounds originated in drug discovery projects directed against defined human proteins, and computational analyses have suggested some level of enrichment among TCAMS hits of inhibitors acting against certain human targets, most notably protein and lipid kinases. This suggests that the antimalarial targets for such compounds could be the Plasmodium orthologs of those kinases. In this chapter the existing information on protein and phosphatidylinositol kinase inhibitors present in the TCAMS is revised and expanded, and the compounds are grouped into chemical families. Their structural similarity to inhibitors currently used in the clinical setting, or which are being developed as drug leads, are also exemplified. The most probable phylogenetic and homology relationships between P. falciparum kinases and human enzymes are updated and the known human targets of TCAMS compounds mapped onto their closest orthologs in the parasite's kinome. This information can be used to generate target hypotheses for the antimalarial mode of action of the compounds. Finally, some experimental approaches are outlined that can be deployed to test theoretical target predictions and to generate alternative hypotheses, which can be corroborated in live parasites.