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
Abstract
Abstract 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 ( Pf PI4Kβ), 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 Pf PI4Kβ 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.
Article Details
Authors (34)
John G. Woodland
Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa
Dina Coertzen
Department of Biochemistry, Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria Hatfield 0028 South Africa
Kathryn J. Wicht
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 Rondebosch, Cape Town 7701 South Africa
Virginia Franco Hidalgo
GlaxoSmithKline Tres Cantos Medicines Development Campus Madrid Spain
Charisse Flerida A. Pasaje
Luiz C. Godoy
Department of Biological Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
Tarrick Qahash
Mmakwena M. Mmonwa
Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa
Godwin A. Dziwornu
Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa
Lynn Wambua
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
Sarah Harries
Department of Chemistry University of Cape Town Rondebosch Cape Town 7701 South Africa
Constance M. Korkor
Department of Chemistry University of Cape Town Rondebosch Cape Town 7701 South Africa
Mathew Njoroge
Liezl Krugmann
Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa
Dale Taylor
Holistic Drug Discovery and Development (H3D) Centre University of Cape Town Rondebosch Cape Town 7701 South Africa
Meta Leshabane
Department of Biochemistry, Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria Hatfield 0028 South Africa
Henrico Langeveld
Department of Biochemistry, Genetics and Microbiology Hatfield Pretoria 0028 South Africa
Tayla Rabie
Department of Biochemistry, Genetics and Microbiology Hatfield Pretoria 0028 South Africa
Janette Reader
Department of Biochemistry, Genetics and Microbiology Institute for Sustainable Malaria Control University of Pretoria Hatfield 0028 South Africa
Mariëtte van der Watt
Institute for Sustainable Malaria Control University of Pretoria Hatfield Pretoria 0028 South Africa
Nelius Venter
Wits Research Institute for Malaria Faculty of Health Sciences University of the Witwatersrand Johannesburg 2193 South Africa
Erica Erlank
Wits Research Institute for Malaria Faculty of Health Sciences University of the Witwatersrand Johannesburg 2193 South Africa
Ayesha S. Aswat
Wits Research Institute for Malaria Faculty of Health Sciences University of the Witwatersrand Johannesburg 2193 South Africa
Lizette L. Koekemoer
Wits Research Institute for Malaria Faculty of Health Sciences University of the Witwatersrand Johannesburg 2193 South Africa
Tomas Yeo
Jin H. Jeon
Department of Microbiology and Immunology, Columbia University Medical Center
David A. Fidock
Department of Microbiology and Immunology, Columbia University Medical Center
Francisco Javier Gamo
GlaxoSmithKline Tres Cantos Medicines Development Campus Madrid Spain
Sergio Wittlin
Swiss Tropical and Public Health Institute
Jacquin C. Niles
Manuel Llinás
Lauren B. Coulson
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 Rondebosch, Cape Town 7701 South Africa
Lyn‐Marié Birkholtz
Department of Biochemistry, Genetics and Microbiology Hatfield Pretoria 0028 South Africa
Kelly Chibale