Human Aurora kinase inhibitor Hesperadin reveals epistatic interaction between Plasmodium falciparum PfArk1 and PfNek1 kinases
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Date
Authors
Morahan, Belinda J.
Abrie, Clarissa
Al-Hasani, Keith
Batty, Mitchell B.
Corey, Victoria
Cowell, Anne N.
Niemand, Jandeli
Winzeler, Elizabeth A.
Birkholtz, Lyn-Marie
Doerig, Christian
Journal Title
Journal ISSN
Volume Title
Publisher
Nature Research
Abstract
Mitosis has been validated by numerous anti-cancer drugs as being a druggable process, and
selective inhibition of parasite proliferation provides an obvious opportunity for therapeutic
intervention against malaria. Mitosis is controlled through the interplay between several
protein kinases and phosphatases. We show here that inhibitors of human mitotic kinases
belonging to the Aurora family inhibit P. falciparum proliferation in vitro with various potencies, and that a genetic selection for mutant parasites resistant to one of the drugs,
Hesperadin, identifies a resistance mechanism mediated by a member of a different kinase
family, PfNek1 (PF3D7_1228300). Intriguingly, loss of PfNek1 catalytic activity provides
protection against drug action. This points to an undescribed functional interaction between
Ark and Nek kinases and shows that existing inhibitors can be used to validate additional
essential and druggable kinase functions in the parasite.
Description
Keywords
Chemical genetics, Target identification, Human mitotic kinases, Aurora kinase inhibitor, Hesperadin, Plasmodium falciparum
Sustainable Development Goals
Citation
Morahan, B.J., Abrie, C., Al-Hasani, K. et al. Human Aurora kinase inhibitor Hesperadin reveals epistatic interaction between Plasmodium falciparum PfArk1 and PfNek1 kinases. Communications Biology 3, 701 (2020). https://doi.org/10.1038/s42003-020-01424-z.