Woodland John G, Coertzen Dina, Wicht Kathryn J, Hidalgo Virginia Franco, Pasaje Charisse Flerida A, Godoy Luiz C, Qahash Tarrick, Mmonwa Mmakwena M, Dziwornu Godwin A, Wambua Lynn, Harries Sarah, Korkor Constance M, Njoroge Mathew, Krugmann Liezl, Taylor Dale, Leshabane Meta, Langeveld Henrico, Rabie Tayla, Reader Janette, van der Watt Mariëtte, Venter Nelius, Erlank Erica, Aswat Ayesha S, Koekemoer Lizette L, Yeo Tomas, Jeon Jin H, Fidock David A, Gamo Francisco Javier, Wittlin Sergio, Niles Jacquin C, Llinas Manuel, Coulson Lauren B, Birkholtz Lyn-Marié, Chibale Kelly
Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, Cape Town, 7701, South Africa.
South African Medical Research Council Drug Discovery and Development Research Unit, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, 7925, South Africa.
Angew Chem Int Ed Engl. 2025 Jul 7;64(28):e202425206. doi: 10.1002/anie.202425206. Epub 2025 May 15.
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) 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.
新型抗人类疟原虫化合物对于有效控制和消除疟疾至关重要。在此，我们研究了咪唑喹啉酮类化合物AZD0156（MMV1580483），它是一种人类共济失调毛细血管扩张症突变（ATM）激酶抑制剂，作为抗癌药物已完成I期临床试验。我们验证了其对人类宿主体内恶性疟原虫两种主要形态的体外活性，即无性血液（有症状）阶段和有性配子体（传播）阶段。抗性筛选、交叉抗性、生化及条件性基因敲低研究表明，AZD0156抑制恶性疟原虫磷脂酰肌醇4-激酶IIIβ型（PfPI4Kβ），这是一个经临床验证的疟疾治疗靶点。代谢扰动、固定比例等效线图、杀伤动力学及形态学评估将AZD0156的抑制作用与其他已知的PI4Kβ抑制剂相关联。该化合物在伯氏疟原虫小鼠疟疾感染模型中显示出良好的体内药代动力学特性及81%的抗疟疗效（4×50mg/kg）。重要的是，针对与PfPI4Kβ抑制剂MMV390048相关的胚胎发育毒性所涉及的人类激酶（MAP4K4、MINK1），测定出其生化特征更纯净。这种改善的激酶选择性特征以及与其他PI4Kβ抑制剂的结构差异，连同其多阶段抗疟活性和良好的药代动力学特性，使得AZD0156成为通过药物化学优化方法进行基于靶点的抗疟疾药物重新定位的有吸引力的候选物。
