Novel Inhibitors of Plasmodium Phosphatidylinositol 4-kinase IIIβ with Low Propensity for Resistance: Life Cycle Stage Activity and In Vivo Efficacy in a Humanized Mouse Malaria Infection Model

  • J Med Chem. 2025 Aug 28;68(16):17736-17751. doi: 10.1021/acs.jmedchem.5c01417.
Godwin A Dziwornu  1 ,  Mmakwena M Mmonwa  2 ,  Dina Coertzen  3 ,  Liezl Krugmann  4 ,  Nicolaas Salomane  4 ,  Meta Leshabane  5 ,  Jean Thomas  3 ,  Shante da Rocha  3 ,  Janette Reader  3 ,  Keabetswe Masike  4 ,  Mathew Njoroge  4 ,  Nicole Sevilleno  5 ,  Rachael Coyle  5 ,  Nonlawat Boonyalai  6 ,  Emily Mayville  7  8 ,  Marcus C S Lee  5  6 ,  David A Fidock  7  8 ,  Lauren B Coulson  4 ,  John G Woodland  1  9 ,  Kathryn J Wicht  1  9 ,  Sandeep R Ghorpade  1 ,  Lyn-Marié Birkholtz  3  10 ,  Kelly Chibale  1  9
Affiliations
  • 1. Holistic Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
  • 2. Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
  • 3. Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria 0028, South Africa.
  • 4. Holistic Drug Discovery and Development Centre (H3D), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town 7925, South Africa.
  • 5. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, U.K.
  • 6. Biological Chemistry and Drug Discovery, Wellcome Centre for Anti-Infectives Research, University of Dundee, Dundee DD1 5EH, U.K.
  • 7. Department of Microbiology and Immunology, Columbia University Medical Center, Hammer Health Sciences Center, 701 W. 168th Street, New York, New York 10032, United States.
  • 8. Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 9. 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 7701, South Africa.
  • 10. Department of Biochemistry, Stellenbosch University, Matieland, Stellenbosch 7601, South Africa.
PMID: 40811478 DOI: 10.1021/acs.jmedchem.5c01417
Abstract

Anticancer ATP-competitive inhibitors are a promising source of new starting points for antimalarial drug discovery. Herein, we present a novel antimalarial chemotype based on the Anticancer human ataxia-telangiectasia-mutated (ATM) kinase inhibitor AZD0156. This class inhibits phosphatidylinositol 4-kinase IIIβ (PI4K) in the human malaria Parasite Plasmodium, demonstrating remarkable activities against all stages of the Plasmodium falciparum life cycle. The current series exhibited a lower propensity for resistance and toxicity compared to previous Plasmodium PI4K inhibitors. The lead compound 18 was efficacious in a humanized NOD-scid IL-2Rγnull mouse model of P. falciparum malaria, with an ED90 value of 4.6 mg kg-1.

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