The ATM Kinase Inhibitor AZD0156 Is a Potent Inhibitor of Plasmodium Phosphatidylinositol 4‐Kinase (PI4Kβ) and Is an Attractive Candidate for Medicinal Chemistry Optimization Against Malaria

• DOI: 10.1002/ange.202425206
• Publication Date: 2025-05-03T07:04:33Z
• Authors: John G. Woodland; Dina Coertzen; Kathryn J. Wicht; Virginia Franco H...; Charisse Flerida ...; Luiz C. Godoy; Tarrick Qahash; Mmakwena M. Mmonwa; Godwin A. Dziwornu; Lynn Wambua; Sarah Harries; Constance M. Korkor; Mathew Njoroge; Liezl Krugmann; Dale Taylor; Meta Leshabane; Henrico Langeveld; Tayla Rabie; Janette Reader; Mariëtte van der ...; Nelius Venter; Erica Erlank; Ayesha S. Aswat; Lizette L. Koekemoer; Tomas Yeo; Jin H. Jeon; David A. Fidock; Francisco Javier ...; Sergio Wittlin; Jacquin C. Niles; Manuel Llinas; Lauren B. Coulson; Lyn‐Marié Birkholtz; Kelly Chibale

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.