The ATM kinase inhibitor AZD0156 is a potent inhibitor of Plasmodium falciparum phosphatidylinositol 4-kinase (PI4Kβ) and is an attractive candidate for medicinal chemistry optimization against malaria

dc.contributor.authorWoodland, John G.
dc.contributor.authorCoertzen, Dina
dc.contributor.authorWicht, Kathryn J.
dc.contributor.authorHidalgo, Virginia Franco
dc.contributor.authorPasaje, Charisse Flerida A.
dc.contributor.authorGodoy, Luiz C.
dc.contributor.authorQahash, Tarrick
dc.contributor.authorMmonwa, Mmakwena M.
dc.contributor.authorDziwornu, Godwin A.
dc.contributor.authorWambua, Lynn
dc.contributor.authorHarries, Sarah
dc.contributor.authorKorkor, Constance M.
dc.contributor.authorNjoroge, Mathew
dc.contributor.authorKrugmann, Liezl
dc.contributor.authorTaylor, Dale
dc.contributor.authorLeshabane, Meta Kgaogelo
dc.contributor.authorLangeveld, Henrico
dc.contributor.authorRabie, Tayla Anne
dc.contributor.authorReader, Janette
dc.contributor.authorVan der Watt, Mariette Elizabeth
dc.contributor.authorVenter, Nelius
dc.contributor.authorErlank, Erica
dc.contributor.authorAswat, Ayesha S.
dc.contributor.authorKoekemoer, Lizette L.
dc.contributor.authorYeo, Tomas
dc.contributor.authorJeon, Jin H.
dc.contributor.authorFidock, David A.
dc.contributor.authorGamo, Francisco Javier
dc.contributor.authorWittlin, Sergio
dc.contributor.authorNiles, Jacquin C.
dc.contributor.authorLlinas, Manuel
dc.contributor.authorCoulson, Lauren B.
dc.contributor.authorBirkholtz, Lyn-Marie
dc.contributor.authorChibale, Kelly
dc.contributor.emaillynmarie.birkholtz@up.ac.za
dc.date.accessioned2025-07-16T06:52:41Z
dc.date.available2025-07-16T06:52:41Z
dc.date.issued2025-07
dc.descriptionDATA AVAILABILITY STATEMENT : The data that support the findings of this study are available from the corresponding authors upon reasonable request.
dc.description.abstractNew compounds targeting human malaria parasites are critical for effective malaria control and elimination. Here, we pursued the imidazoquinolinone AZD0156 (MMV1580483), a human ataxia-telangiectasia mutated (ATM) kinase inhibitor that completed Phase I clinical trials as an anticancer agent. We validated its in vitro activity against the two main forms of the Plasmodium falciparum parasite in the human host, viz. the asexual blood (symptomatic) stage and sexual gametocyte (transmission) stage. Resistance selection, cross-resistance, biochemical, and conditional knockdown studies revealed that AZD0156 inhibits P. falciparum phosphatidylinositol 4-kinase type III beta (PfPI4Kβ), a clinically-validated target for the treatment of malaria. Metabolic perturbations, fixed-ratio isobolograms, killing kinetics and morphological evaluation correlated AZD0156 inhibition with other known PI4Kβ inhibitors. The compound showed favorable in vivo pharmacokinetic properties and 81% antimalarial efficacy (4 × 50 mg kg−1) in a P. berghei mouse malaria infection model. Importantly, a cleaner biochemical profile was measured against human kinases (MAP4K4, MINK1) implicated in embryofoetal developmental toxicity associated with the PfPI4Kβ inhibitor MMV390048. This improved kinase selectivity profile and structural differentiation from other PI4Kβ inhibitors, together with its multistage antiplasmodial activity and favorable pharmacokinetic properties, makes AZD0156 an attractive candidate for target-based drug repositioning against malaria via a medicinal chemistry optimization approach.
dc.description.departmentBiochemistry, Genetics and Microbiology (BGM)
dc.description.departmentUP Centre for Sustainable Malaria Control (UP CSMC)
dc.description.librarianhj2025
dc.description.sdgSDG-03: Good health and well-being
dc.description.sponsorshipMedicines for Malaria Venture; Future Leaders−African Independent Research (FLAIR); the UK Government's Global Challenges Research ;. The National Institute of Allergy and Infectious Diseases of the National Institutes of Health; Gates Foundation; South African Medical Research Council; Department of Science and Innovation (SAMRC-GIPD) Drug Discovery for Malaria Elimination; The Department of Science and Innovation and the National Research Foundation South African Research Chair.
dc.description.urihttps://onlinelibrary.wiley.com/journal/15213773
dc.identifier.citationWoodland, J.G., Coertzen, D., Wicht, K.J. et al. 2025, 'The ATM kinase inhibitor AZD0156 is a potent inhibitor of Plasmodium falciparum phosphatidylinositol 4-kinase (PI4Kβ) and is an attractive candidate for medicinal chemistry optimization against malaria', Angewandte Chemie - International Edition, vol. 64, no. 28, art. e202425206, doi : 10.1002/anie.202425206.
dc.identifier.issn0044-8249 (print)
dc.identifier.issn1521-3757 (online)
dc.identifier.other10.1002/anie.202425206
dc.identifier.urihttp://hdl.handle.net/2263/103387
dc.language.isoen
dc.publisherWiley
dc.rights© 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License.
dc.subjectAntiplasmodial
dc.subjectBiological activity
dc.subjectMalaria
dc.subjectMedicinal chemistry
dc.subjectPhosphatidylinositol 4-kinase type III beta (PI4Kβ)
dc.subjectRepositioning
dc.titleThe ATM kinase inhibitor AZD0156 is a potent inhibitor of Plasmodium falciparum phosphatidylinositol 4-kinase (PI4Kβ) and is an attractive candidate for medicinal chemistry optimization against malaria
dc.typeArticle

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