Targeting Aurora kinases as essential cell cycle regulators to deliver multi-stage antimalarials against Plasmodium falciparum

Kinases that play critical roles in the development and adaptation of Plasmodium falciparum present novel opportunities for chemotherapeutic intervention. Of particular interest are mitotic kinases that regulate the proliferation of the parasites by controlling nuclear division, segregation and cytokinesis. We evaluated the potential of human Aurora kinase (Aur) inhibitors to inhibit P. falciparum development by targeting members of the Aurora-related kinase (Ark) family in this parasite. Several human AurB inhibitors exhibited multistage potency (<250 nM) against all proliferative stages of parasite development, including asexual blood stages, liver schizonts and male gametes. Among the most potent compounds, hesperadin and AT83 exhibit >1000x selectivity towards the parasite without concerns about mammalian cell toxicity. Importantly, we identified Pf Ark1 as the principal vulnerable Ark family member, with specific inhibition of Pf Ark1 as the primary target for hesperadin and the human anaplastic lymphoma kinase (ALK) inhibitor TAE684. Hesperadin’s whole-cell and protein activity validates it as a unique Pf Ark1 tool compound. Inhibition of Pf Ark1 results in the parasite’s inability to complete mitotic processes, presenting with unsegregated, multi-lobed nuclei caused by aberrant microtubule organization. This suggests that Pf Ark1 is the main Aur mitotic kinase in proliferative stages of Plasmodium , characterized by bifunctional AurA and B activity. This paves the way for drug discovery campaigns based on hesperadin targeting Pf Ark1.