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

Godwin A. Dziwornu; Mmakwena M. Mmonwa; Dina Coertzen; Liezl Krugmann; Nicolaas Salomane; Meta Leshabane; Jean Thomas; Shante da Rocha; Janette Reader; Keabetswe Masike; Mathew Njoroge; Nicole Sevilleno; Rachael Coyle; Nonlawat Boonyalai; Emily Mayville; Marcus C.S. Lee; David A. Fidock; Lauren B. Coulson; John G. Woodland; Kathryn J. Wicht; Sandeep R. Ghorpade; Lyn Marié Birkholtz; Kelly Chibale

doi:10.1021/acs.jmedchem.5c01417

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

Godwin A. Dziwornu
, Mmakwena M. Mmonwa
, Dina Coertzen
, Liezl Krugmann
, Nicolaas Salomane
, Meta Leshabane
, Jean Thomas
, Shante da Rocha
, Janette Reader
, Keabetswe Masike
, Mathew Njoroge
, Nicole Sevilleno
, Rachael Coyle
, Nonlawat Boonyalai
, Emily Mayville
, Marcus C.S. Lee
, David A. Fidock
, Lauren B. Coulson
, John G. Woodland
, Kathryn J. Wicht

Sandeep R. Ghorpade, Lyn Marié Birkholtz, Kelly Chibale (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

72 Downloads (Pure)

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 ED₉₀value of 4.6 mg kg^-1.

Original language	English
Pages (from-to)	17736-17751
Number of pages	16
Journal	Journal of Medicinal Chemistry
Volume	68
Issue number	16
Early online date	14 Aug 2025
DOIs	https://doi.org/10.1021/acs.jmedchem.5c01417
Publication status	Published - 28 Aug 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.5c01417Licence: CC BY

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©2025 The Authors. Published by American Chemical Societ
Final published version, 3.86 MBLicence: CC BY

Cite this

Dziwornu, G. A., Mmonwa, M. M., Coertzen, D., Krugmann, L., Salomane, N., Leshabane, M., Thomas, J., da Rocha, S., Reader, J., Masike, K., Njoroge, M., Sevilleno, N., Coyle, R., Boonyalai, N., Mayville, E., Lee, M. C. S., Fidock, D. A., Coulson, L. B., Woodland, J. G., ... Chibale, K. (2025). 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. Journal of Medicinal Chemistry, 68(16), 17736-17751. https://doi.org/10.1021/acs.jmedchem.5c01417

@article{ce55139282fa48d19c64d3fcd5078691,

title = "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",

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 ED90value of 4.6 mg kg-1.",

author = "Dziwornu, \{Godwin A.\} and Mmonwa, \{Mmakwena M.\} and Dina Coertzen and Liezl Krugmann and Nicolaas Salomane and Meta Leshabane and Jean Thomas and \{da Rocha\}, Shante and Janette Reader and Keabetswe Masike and Mathew Njoroge and Nicole Sevilleno and Rachael Coyle and Nonlawat Boonyalai and Emily Mayville and Lee, \{Marcus C.S.\} and Fidock, \{David A.\} and Coulson, \{Lauren B.\} and Woodland, \{John G.\} and Wicht, \{Kathryn J.\} and Ghorpade, \{Sandeep R.\} and Birkholtz, \{Lyn Mari{\'e}\} and Kelly Chibale",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors. Published by American Chemical Society",

year = "2025",

month = aug,

day = "28",

doi = "10.1021/acs.jmedchem.5c01417",

language = "English",

volume = "68",

pages = "17736--17751",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "16",

}

Dziwornu, GA, Mmonwa, MM, Coertzen, D, Krugmann, L, Salomane, N, Leshabane, M, Thomas, J, da Rocha, S, Reader, J, Masike, K, Njoroge, M, Sevilleno, N, Coyle, R, Boonyalai, N, Mayville, E, Lee, MCS, Fidock, DA, Coulson, LB, Woodland, JG, Wicht, KJ, Ghorpade, SR, Birkholtz, LM & Chibale, K 2025, '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', Journal of Medicinal Chemistry, vol. 68, no. 16, pp. 17736-17751. https://doi.org/10.1021/acs.jmedchem.5c01417

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. / Dziwornu, Godwin A.; Mmonwa, Mmakwena M.; Coertzen, Dina et al.
In: Journal of Medicinal Chemistry, Vol. 68, No. 16, 28.08.2025, p. 17736-17751.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Novel Inhibitors of Plasmodium Phosphatidylinositol 4-kinase IIIβ with Low Propensity for Resistance

T2 - Life Cycle Stage Activity and In Vivo Efficacy in a Humanized Mouse Malaria Infection Model

AU - Dziwornu, Godwin A.

AU - Mmonwa, Mmakwena M.

AU - Coertzen, Dina

AU - Krugmann, Liezl

AU - Salomane, Nicolaas

AU - Leshabane, Meta

AU - Thomas, Jean

AU - da Rocha, Shante

AU - Reader, Janette

AU - Masike, Keabetswe

AU - Njoroge, Mathew

AU - Sevilleno, Nicole

AU - Coyle, Rachael

AU - Boonyalai, Nonlawat

AU - Mayville, Emily

AU - Lee, Marcus C.S.

AU - Fidock, David A.

AU - Coulson, Lauren B.

AU - Woodland, John G.

AU - Wicht, Kathryn J.

AU - Ghorpade, Sandeep R.

AU - Birkholtz, Lyn Marié

AU - Chibale, Kelly

PY - 2025/8/28

Y1 - 2025/8/28

N2 - 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 ED90value of 4.6 mg kg-1.

AB - 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 ED90value of 4.6 mg kg-1.

UR - https://www.scopus.com/pages/publications/105014456324

U2 - 10.1021/acs.jmedchem.5c01417

DO - 10.1021/acs.jmedchem.5c01417

M3 - Article

C2 - 40811478

AN - SCOPUS:105014456324

SN - 0022-2623

VL - 68

SP - 17736

EP - 17751

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 16

ER -

Dziwornu GA, Mmonwa MM, Coertzen D, Krugmann L, Salomane N, Leshabane M et al. 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. Journal of Medicinal Chemistry. 2025 Aug 28;68(16):17736-17751. Epub 2025 Aug 14. doi: 10.1021/acs.jmedchem.5c01417

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

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