The ATM Kinase Inhibitor AZD0156 Is a Potent Inhibitor of <i>Plasmodium</i> Phosphatidylinositol 4‐Kinase (PI4Kβ) and Is an Attractive Candidate for Medicinal Chemistry Optimization Against Malaria
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<sup>-1</sup>) 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.
Authors
- John G. Woodland (ORCID: https://orcid.org/0000-0001-6273-5596)
- Francisco‐Javier Gamo (ORCID: https://orcid.org/0000-0002-1854-2882)
- Constance M. Korkor (ORCID: https://orcid.org/0000-0001-6925-8905)
- Charisse Flerida A. Pasaje (ORCID: https://orcid.org/0000-0002-9780-3680)
- Tarrick Qahash (ORCID: https://orcid.org/0000-0003-2891-3090)
- Lizette L. Koekemoer (ORCID: https://orcid.org/0000-0003-4236-6345)
- Sergio Wittlin (ORCID: https://orcid.org/0000-0002-0811-0912)
- Mathew Njoroge (ORCID: https://orcid.org/0000-0003-1276-2224)
- Godwin Akpeko Dziwornu (ORCID: https://orcid.org/0000-0003-1668-8818)
- Dale Taylor (ORCID: https://orcid.org/0000-0001-7402-0563)
- Manuel Llinás (ORCID: https://orcid.org/0000-0002-6173-5882)
- Henrico Langeveld (ORCID: https://orcid.org/0000-0002-5193-9742)
- Janette Reader (ORCID: https://orcid.org/0000-0001-9026-0583)
- Lauren B. Coulson (ORCID: https://orcid.org/0000-0003-4699-0428)
- Tomas Yeo (ORCID: https://orcid.org/0000-0003-2923-6060)
- Jacquin C. Niles (ORCID: https://orcid.org/0000-0002-6250-8796)
- Dina Coertzen (ORCID: https://orcid.org/0000-0002-8408-244X)
- Luiz C. Godoy (ORCID: https://orcid.org/0000-0001-6981-377X)
- Kelly Chibale (ORCID: https://orcid.org/0000-0002-1327-4727)
- Kathryn J. Wicht (ORCID: https://orcid.org/0000-0001-6145-9956)
- Ayesha S. Aswat (ORCID: https://orcid.org/0000-0002-5326-6764)
- Erica Erlank (ORCID: https://orcid.org/0000-0002-9687-6095)
- Jin Yong Jeon (ORCID: https://orcid.org/0000-0002-1469-4520)
- David A. Fidock (ORCID: https://orcid.org/0000-0001-6753-8938)
- Mmakwena M. Mmonwa
- Nelius Venter (ORCID: https://orcid.org/0009-0000-9109-7079)
- Mariëtte van der Watt (ORCID: https://orcid.org/0000-0002-9933-8647)
- Lyn‐Marié Birkholtz (ORCID: https://orcid.org/0000-0001-5888-2905)
- Liezl Gibhard (ORCID: https://orcid.org/0000-0003-0089-2136)
- Meta Leshabane (ORCID: https://orcid.org/0000-0001-6885-1483)
- Lynn Wambua (ORCID: https://orcid.org/0000-0002-6218-199X)
- Tayla Rabie
- Sarah Harries
- Virginia Franco Hidalgo
Institutions
- National Health Laboratory Service (ZA)
- South African Medical Research Council (ZA)
- Pennsylvania State University (US)
- University of Cape Town (ZA)
- Swiss Tropical and Public Health Institute (CH)
- University of Basel (CH)
- University of the Witwatersrand (ZA)
- Stellenbosch University (ZA)
- Columbia University Irving Medical Center (US)
- GlaxoSmithKline (India) (IN)
- GlaxoSmithKline (Spain) (ES)
- Massachusetts Institute of Technology (US)
- University of Pretoria (ZA)
Publication Details
- Journal
- Angewandte Chemie International Edition
- Published
- 2025-05-03
- DOI
- https://doi.org/10.1002/anie.202425206
- Citations
- 6
- Primary Topic
- HIV/AIDS drug development and treatment
- Type
- article
- Field-Weighted Citation Impact
- 8.38
Funders
- Bill and Melinda Gates Foundation
- Government of the United Kingdom
- National Research Foundation
- South African Medical Research Council
- Medicines for Malaria Venture
- African Academy of Sciences
- National Institutes of Health
- Huck Institutes of the Life Sciences
- Medical Research Council
- National Institute of Allergy and Infectious Diseases