Human Aurora kinase inhibitor Hesperadin reveals epistatic interaction between Plasmodium falciparum PfArk1 and PfNek1 kinases
| Autor: | Lyn-Marie Birkholtz, Keith Al-Hasani, Mitchell B Batty, Belinda Joan Morahan, Jose F. Garcia-Bustos, Victoria C. Corey, Christian Doerig, Elizabeth A. Winzeler, Clarissa Abrie, Anne N. Cowell, Jandeli Niemand |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Indoles Plasmodium falciparum Protozoan Proteins Druggability Aurora inhibitor Medicine (miscellaneous) Drug action Biology Article Chemical genetics General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Aurora Kinases Target identification Humans lcsh:QH301-705.5 Mitosis Sulfonamides Kinase Hesperadin Epistasis Genetic biology.organism_classification Cell biology NIMA-Related Kinase 1 030104 developmental biology lcsh:Biology (General) chemistry 030220 oncology & carcinogenesis General Agricultural and Biological Sciences NIMA-Related Kinases |
| Zdroj: | Communications Biology Communications Biology, Vol 3, Iss 1, Pp 1-10 (2020) |
| ISSN: | 2399-3642 |
| Popis: | 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. Morahan et al. investigate inhibitors of human mitotic kinases in P. falciparum and show a resistance mechanism to the drug Hesperadin through an epistatic interaction between the PfArk1 and PfNek1 kinases. This study demonstrates that existing inhibitors can be used to validate additional essential and druggable kinase functions in the parasite. |
| Databáze: | OpenAIRE |
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