TY - JOUR
T1 - Targeting Aurora Kinases as Essential Cell-Cycle Regulators to Deliver Multi-Stage Antimalarials Against Plasmodium Falciparum
AU - Langeveld, Henrico
AU - Maepa, Keletso
AU - Maree, Marché
AU - Thibaud, Jessica L.
AU - Salomane, Nicolaas
AU - Bridgwater, Rosie
AU - Famodimu, Mufuliat T.
AU - Godoy, Luiz C.
AU - Pasaje, Charisse Flerida A.
AU - Boonyalai, Nonlawat
AU - de Souza, Mariana Laureano
AU - Fong, Justin
AU - Rabie, Tayla
AU - van der Watt, Mariëtte
AU - Theart, Rensu P.
AU - Ghidelli-Disse, Sonja
AU - Niles, Jacquin C.
AU - Lee, Marcus C.S.
AU - Winzeler, Elizabeth A.
AU - Delves, Michael J.
AU - Chibale, Kelly
AU - Wicht, Kathryn J.
AU - Coulson, Lauren B.
AU - Birkholtz, Lyn Marié
N1 - Publisher Copyright:
© 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.
PY - 2025/12/16
Y1 - 2025/12/16
N2 - Kinases play critical roles in the development and adaptation of Plasmodium falciparum and present novel opportunities for chemotherapeutic intervention. 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 prevent 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. The most potent compounds, hesperadin, TAE684, and AT83, exhibited > 1000x selectivity towards the parasite. Importantly, we identified PfArk1 as the principal vulnerable Ark family member, with specific inhibition of PfArk1 as the primary target for hesperadin. Hesperadin's whole-cell and protein activity validates it as a unique PfArk1 tool compound. Inhibition of PfArk1 results in the parasite's inability to complete mitotic processes, presenting with unsegregated, multi-lobed nuclei caused by aberrant microtubule organization. This suggests PfArk1 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 PfArk1.
AB - Kinases play critical roles in the development and adaptation of Plasmodium falciparum and present novel opportunities for chemotherapeutic intervention. 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 prevent 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. The most potent compounds, hesperadin, TAE684, and AT83, exhibited > 1000x selectivity towards the parasite. Importantly, we identified PfArk1 as the principal vulnerable Ark family member, with specific inhibition of PfArk1 as the primary target for hesperadin. Hesperadin's whole-cell and protein activity validates it as a unique PfArk1 tool compound. Inhibition of PfArk1 results in the parasite's inability to complete mitotic processes, presenting with unsegregated, multi-lobed nuclei caused by aberrant microtubule organization. This suggests PfArk1 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 PfArk1.
KW - Anti-cancer inhibitors
KW - Antimalarial drug discovery
KW - Aurora kinase
KW - Cell cycle regulation
KW - Plasmodium
UR - https://www.scopus.com/pages/publications/105019675665
U2 - 10.1002/anie.202518493
DO - 10.1002/anie.202518493
M3 - Article
C2 - 41131905
AN - SCOPUS:105019675665
SN - 1433-7851
VL - 64
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 51
M1 - e202518493
ER -
