The human Aurora kinase inhibitor danusertib is a lead compound for anti-trypanosomal drug discovery via target repurposing

New drugs for neglected tropical diseases such as human African trypanosomiasis (HAT) are needed, yet drug discovery efforts are not often focused on this area due to cost. Target repurposing, achieved by the matching of essential parasite enzymes to those human enzymes that have been successfully inhibited by small molecule drugs, provides an attractive means by which new drug optimization programs can be pragmatically initiated. In this report we describe our results in repurposing an established class of human Aurora kinase inhibitors, typified by danusertib (1), which we have observed to be an inhibitor of trypanosomal Aurora kinase 1 (TbAUK1) and effective in parasite killing in vitro. Informed by homology modeling and docking, a series of analogs of 1 were prepared that explored the scope of the chemotype and provided a nearly 25-fold improvement in cellular selectivity for parasite cells over human cells.

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► We assessed a class of human Aurora kinase inhibitors against Trypanosoma brucei.
► The human Aurora inhibitor danusertib inhibits TbAUK1 and T. brucei growth.
► Analogs of danusertib were designed based on a TbAUK1 homology model.
► New analogs show improved selectivity for killing T. brucei cells over host cells.
► We show that target repurposing can provide a rapid start for NTD drug discovery.