The antimalarial drug arsenal has historically benefitted from the phenotypic screening approach to identify lead molecules in the search for new drugs; with artemisinin being one of the most notable examples. As part of an effort to discover new antimalarial drugs we screened the Novartis natural product library to identify a spiroindolone hit which was the focus of a lead optimization effort resulting in the discovery and development of KAE609 (NITD609). In a parallel effort, we applied a full genome analysis of spiroindolone-resistant parasites to conclude that the spiroindolones work though a unique mode of action, namely the inhibition of a P-type Plasmodium falciparum ATPase4 (a Na+ efflux pump). Disruption of Na+ homeostasis by the spiroindolones was shown to rapidly lead to parasite death. KAE609 represents the first antimalarial chemotype working though a novel mechanism of action to enter Phase II clinical trials in over 20 years.

Discovery, optimization, and mode of action of spiroindolone antimalarials

247th National Meeting (2014)

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