Zero Hunger (SDG 2), Good Health & Well-being (SDG 3)
The ATM Kinase Inhibitor AZD0156 is a potent inhibitor of Plasmodium Phosphatidylinositol 4-Kinase (PI4Kβ) and is an attractive candidate for repositioning against malaria John G. Woodland 1,2,3+ , Dina Coertzen 4,5+ , Kathryn J. Wicht 1,2,3 , Virginia Franco Hidalgo 6 , Charisse Flerida A. Pasaje 7 , Luiz C. Godoy 7 , Tarrick Qahash 8,9 , Mmakwena M. Mmonwa 1 , Godwin A. Dziwornu 1 , Lynn Wambua 2,3 , Sarah Harries3, Constance M. Korkor 3 , Mathew Njoroge 1 , Liezl Gibhard 1 , Dale Taylor 1 , Meta Leshabane 4,5 , Henrico Langeveld 4,5 , Tayla Rabie 4,5 , Janette Reader 4,5 , Mariëtte van der Watt 5 , Nelius Venter 10,11 , Erica Erlank 10,11 , Ayesha S. Aswat 10,11 , Lizette L. Koekemoer 10,11 , Tomas Yeo 12,13 , Jin H. Jeon 12,13 , David A. Fidock 12,13 , Francisco Javier Gamo 6 , Sergio Wittlin 14,15 , Jacquin C. Niles 7 , Manuel Llinas 8,9 , Lauren B. Coulson 1,2 , Lyn-Marié Birkholtz 4,5,16* and Kelly Chibale 1,2,3* 1 Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, Cape Town, 7701, South Africa. 2 South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925, South Africa. 3 Department of Chemistry, University of Cape Town, Rondebosch, Cape Town, 7701, South Africa. 4 Department of Biochemistry, Genetics and Microbiology, University of Pretoria, South Africa. 5 Institute for Sustainable Malaria Control, School of Public Health and Health Systems, University of Pretoria, Hatfield 0028, South Africa. 6 GlaxoSmithKline, Tres Cantos Medicines Development Campus, Madrid, Spain. 7 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. 8 Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA. 9 Huck Center for Malaria Research, Pennsylvania State University, University Park, PA 16802, USA. 10 Wits Research Institute for Malaria, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa. 11 Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases, a Division of the National Health Laboratory Service, Johannesburg 2193, South Africa. 12 Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA. 13 Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA. 14 Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123 Allschwil, Switzerland. 15 University of Basel, 4003, Basel, Switzerland. 16 Department of Biochemistry, Stellenbosch University, Stellenbosch, Matieland, 7602, South Africa. + These authors contributed equally to this work. * Corresponding authors: Kelly Chibale (kelly.chibale@uct.ac.za) and Lyn-Marié Birkholtz (lynmarie.birkholtz@up.ac.za) 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 Plasmodium falciparum activity against the two main forms of the 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 favourable 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 antiplasmodium activity and favourable pharmacokinetic properties, makes AZD0156 an attractive candidate for target-based drug repositioning against malaria. Key words: Malaria, antiplasmodium, phosphatidylinositol 4-kinase type III beta (PI4Kβ), repositioning, chemical biology
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