{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:32:29Z","timestamp":1790937149116,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"28","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"publisher","award":["RD\u201017\u20100047"],"award-info":[{"award-number":["RD\u201017\u20100047"]}],"id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"publisher","award":["RD\u201019\u20100001"],"award-info":[{"award-number":["RD\u201019\u20100001"]}],"id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2025,7,7]]},"abstract":"Abstract<\/jats:title>\n \n New compounds targeting human malaria parasites are critical for effective malaria control and elimination. Here, we pursued the imidazoquinolinone AZD0156 (MMV1580483), a human ataxia\u2010telangiectasia 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\n Plasmodium falciparum<\/jats:italic>\n parasite in the human host, viz. the asexual blood (symptomatic) stage and sexual gametocyte (transmission) stage. Resistance selection, cross\u2010resistance, biochemical, and conditional knockdown studies revealed that AZD0156 inhibits\n P. falciparum<\/jats:italic>\n phosphatidylinositol 4\u2010kinase type III beta (\n Pf<\/jats:italic>\n PI4K\u03b2), a clinically\u2010validated target for the treatment of malaria. Metabolic perturbations, fixed\u2010ratio isobolograms, killing kinetics and morphological evaluation correlated AZD0156 inhibition with other known PI4K\u03b2 inhibitors. The compound showed favorable in vivo pharmacokinetic properties and 81% antimalarial efficacy (4 \u00d7 50 mg kg\n \u22121<\/jats:sup>\n ) in a\n P. berghei<\/jats:italic>\n mouse malaria infection model. Importantly, a cleaner biochemical profile was measured against human kinases (MAP4K4, MINK1) implicated in embryofoetal developmental toxicity associated with the\n Pf<\/jats:italic>\n PI4K\u03b2 inhibitor MMV390048. This improved kinase selectivity profile and structural differentiation from other PI4K\u03b2 inhibitors, together with its multistage antiplasmodial activity and favorable pharmacokinetic properties, makes AZD0156 an attractive candidate for target\u2010based drug repositioning against malaria via a medicinal chemistry optimization approach.\n <\/jats:p>","DOI":"10.1002\/anie.202425206","type":"journal-article","created":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T03:04:32Z","timestamp":1746241472000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The ATM Kinase Inhibitor AZD0156 Is a Potent Inhibitor of\n Plasmodium<\/i>\n Phosphatidylinositol 4\u2010Kinase (PI4K\u03b2) and Is an Attractive Candidate for Medicinal Chemistry Optimization Against Malaria"],"prefix":"10.1002","volume":"64","author":[{"given":"John G.","family":"Woodland","sequence":"first","affiliation":[{"name":"Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa"},{"name":"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"},{"name":"Department of Chemistry University of Cape Town Rondebosch Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Coertzen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria Hatfield 0028 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn J.","family":"Wicht","sequence":"additional","affiliation":[{"name":"Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa"},{"name":"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"},{"name":"Department of Chemistry University of Cape Town Rondebosch Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia Franco","family":"Hidalgo","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Tres Cantos Medicines Development Campus Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charisse Flerida A.","family":"Pasaje","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz C.","family":"Godoy","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarrick","family":"Qahash","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Pennsylvania State University University Park, State College PA 16802 USA"},{"name":"Huck Center for Malaria Research Pennsylvania State University University Park, State College PA 16802 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mmakwena M.","family":"Mmonwa","sequence":"additional","affiliation":[{"name":"Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Godwin A.","family":"Dziwornu","sequence":"additional","affiliation":[{"name":"Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Wambua","sequence":"additional","affiliation":[{"name":"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"},{"name":"Department of Chemistry University of Cape Town Rondebosch Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Harries","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Cape Town Rondebosch Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constance M.","family":"Korkor","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Cape Town Rondebosch Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew","family":"Njoroge","sequence":"additional","affiliation":[{"name":"Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liezl","family":"Krugmann","sequence":"additional","affiliation":[{"name":"Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale","family":"Taylor","sequence":"additional","affiliation":[{"name":"Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meta","family":"Leshabane","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria Hatfield 0028 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrico","family":"Langeveld","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria Hatfield 0028 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tayla","family":"Rabie","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria Hatfield 0028 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janette","family":"Reader","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria Hatfield 0028 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u00ebtte","family":"van der Watt","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria Hatfield 0028 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelius","family":"Venter","sequence":"additional","affiliation":[{"name":"Wits Research Institute for Malaria Faculty of Health Sciences University of the Witwatersrand Johannesburg 2193 South Africa"},{"name":"Centre for Emerging Zoonotic and Parasitic Diseases National Institute for Communicable Diseases a Division of the National Health Laboratory Service Johannesburg 2193 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Erlank","sequence":"additional","affiliation":[{"name":"Wits Research Institute for Malaria Faculty of Health Sciences University of the Witwatersrand Johannesburg 2193 South Africa"},{"name":"Centre for Emerging Zoonotic and Parasitic Diseases National Institute for Communicable Diseases a Division of the National Health Laboratory Service Johannesburg 2193 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayesha S.","family":"Aswat","sequence":"additional","affiliation":[{"name":"Wits Research Institute for Malaria Faculty of Health Sciences University of the Witwatersrand Johannesburg 2193 South Africa"},{"name":"Centre for Emerging Zoonotic and Parasitic Diseases National Institute for Communicable Diseases a Division of the National Health Laboratory Service Johannesburg 2193 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizette L.","family":"Koekemoer","sequence":"additional","affiliation":[{"name":"Wits Research Institute for Malaria Faculty of Health Sciences University of the Witwatersrand Johannesburg 2193 South Africa"},{"name":"Centre for Emerging Zoonotic and Parasitic Diseases National Institute for Communicable Diseases a Division of the National Health Laboratory Service Johannesburg 2193 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Yeo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Columbia University Irving Medical Center New York NY 10032 USA"},{"name":"Center for Malaria Therapeutics and Antimicrobial Resistance Division of Infectious Diseases Department of Medicine Columbia University Irving Medical Center New York NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin H.","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Columbia University Irving Medical Center New York NY 10032 USA"},{"name":"Center for Malaria Therapeutics and Antimicrobial Resistance Division of Infectious Diseases Department of Medicine Columbia University Irving Medical Center New York NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Fidock","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Columbia University Irving Medical Center New York NY 10032 USA"},{"name":"Center for Malaria Therapeutics and Antimicrobial Resistance Division of Infectious Diseases Department of Medicine Columbia University Irving Medical Center New York NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Javier","family":"Gamo","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Tres Cantos Medicines Development Campus Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Wittlin","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute Kreuzstrasse 2 Allschwil 4123 Switzerland"},{"name":"University of Basel Basel 4003 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquin C.","family":"Niles","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Llinas","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Pennsylvania State University University Park, State College PA 16802 USA"},{"name":"Huck Center for Malaria Research Pennsylvania State University University Park, State College PA 16802 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren B.","family":"Coulson","sequence":"additional","affiliation":[{"name":"Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyn\u2010Mari\u00e9","family":"Birkholtz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria Hatfield 0028 South Africa"},{"name":"Department of Biochemistry Stellenbosch University, Stellenbosch Matieland 7602 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Chibale","sequence":"additional","affiliation":[{"name":"Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa"},{"name":"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"},{"name":"Department of Chemistry University of Cape Town Rondebosch Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4381"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112955"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adp5137"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.0c00724"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2022.01.011"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.901971"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00329"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2023.06.001"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dky008"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00772-9"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12782"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdr2.2012"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr500098f"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.11.95"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abo7219"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-13-143"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20629-8"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-54144-x"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad9735"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.0c00566"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00012-18"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10727"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-77644-4"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-18-1394"},{"key":"e_1_2_8_25_1","author":"Pike K. G.","year":"2024","journal-title":"J. Med. Chem."},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b01896"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13071-018-2800-1"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-34964-w"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c01154"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01224-16"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02214\u201017"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04966-3"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12782"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-019-6322-9"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2003.11.021"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01896\u201019"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abg6013"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b01265"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202425206","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T15:23:38Z","timestamp":1767626618000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.202425206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,15]]},"references-count":38,"journal-issue":{"issue":"28","published-print":{"date-parts":[[2025,7,7]]}},"alternative-id":["10.1002\/anie.202425206"],"URL":"https:\/\/doi.org\/10.1002\/anie.202425206","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,15]]},"assertion":[{"value":"2024-12-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202425206"}}