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.author | Woodland, John G. | |
dc.contributor.author | Coertzen, Dina | |
dc.contributor.author | Wicht, Kathryn J. | |
dc.contributor.author | Hidalgo, Virginia Franco | |
dc.contributor.author | Pasaje, Charisse Flerida A. | |
dc.contributor.author | Godoy, Luiz C. | |
dc.contributor.author | Qahash, Tarrick | |
dc.contributor.author | Mmonwa, Mmakwena M. | |
dc.contributor.author | Dziwornu, Godwin A. | |
dc.contributor.author | Wambua, Lynn | |
dc.contributor.author | Harries, Sarah | |
dc.contributor.author | Korkor, Constance M. | |
dc.contributor.author | Njoroge, Mathew | |
dc.contributor.author | Krugmann, Liezl | |
dc.contributor.author | Taylor, Dale | |
dc.contributor.author | Leshabane, Meta Kgaogelo | |
dc.contributor.author | Langeveld, Henrico | |
dc.contributor.author | Rabie, Tayla Anne | |
dc.contributor.author | Reader, Janette | |
dc.contributor.author | Van der Watt, Mariette Elizabeth | |
dc.contributor.author | Venter, Nelius | |
dc.contributor.author | Erlank, Erica | |
dc.contributor.author | Aswat, Ayesha S. | |
dc.contributor.author | Koekemoer, Lizette L. | |
dc.contributor.author | Yeo, Tomas | |
dc.contributor.author | Jeon, Jin H. | |
dc.contributor.author | Fidock, David A. | |
dc.contributor.author | Gamo, Francisco Javier | |
dc.contributor.author | Wittlin, Sergio | |
dc.contributor.author | Niles, Jacquin C. | |
dc.contributor.author | Llinas, Manuel | |
dc.contributor.author | Coulson, Lauren B. | |
dc.contributor.author | Birkholtz, Lyn-Marie | |
dc.contributor.author | Chibale, Kelly | |
dc.contributor.email | lynmarie.birkholtz@up.ac.za | |
dc.date.accessioned | 2025-07-16T06:52:41Z | |
dc.date.available | 2025-07-16T06:52:41Z | |
dc.date.issued | 2025-07 | |
dc.description | DATA AVAILABILITY STATEMENT : The data that support the findings of this study are available from the corresponding authors upon reasonable request. | |
dc.description.abstract | New 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.department | Biochemistry, Genetics and Microbiology (BGM) | |
dc.description.department | UP Centre for Sustainable Malaria Control (UP CSMC) | |
dc.description.librarian | hj2025 | |
dc.description.sdg | SDG-03: Good health and well-being | |
dc.description.sponsorship | Medicines 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.uri | https://onlinelibrary.wiley.com/journal/15213773 | |
dc.identifier.citation | Woodland, 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.issn | 0044-8249 (print) | |
dc.identifier.issn | 1521-3757 (online) | |
dc.identifier.other | 10.1002/anie.202425206 | |
dc.identifier.uri | http://hdl.handle.net/2263/103387 | |
dc.language.iso | en | |
dc.publisher | Wiley | |
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.subject | Antiplasmodial | |
dc.subject | Biological activity | |
dc.subject | Malaria | |
dc.subject | Medicinal chemistry | |
dc.subject | Phosphatidylinositol 4-kinase type III beta (PI4Kβ) | |
dc.subject | Repositioning | |
dc.title | 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.type | Article |
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