The Human Chk1 Inhibitor CHIR-124 Shows Multistage Activity against the Human Malaria Parasite <i>Plasmodium falciparum</i> via Polypharmacological Inhibition of <i>Pf</i> Ark1 and Hemozoin Formation

High Resolution Image Download MS PowerPoint Slide The high burden of malaria and growing resistance to frontline antimalarials demand new drug target combinations with reduced propensities for conferring parasite resistance. An attractive approach for circumventing antimalarial drug resistance is target repurposing, in which known drugs that act through protein targets of human origin that are also active against the human malaria parasite Plasmodium falciparum are exploited to identify novel antimalarial drug targets. Here, we show that the human checkpoint kinase 1 (Chk1) inhibitor CHIR-124 is active in vitro against both drug-sensitive and drug-resistant asexual blood stage parasites and competitively binds to several Plasmodium kinases. The compound also shows moderate activity against both the liver and gametocyte forms of the parasite. Further target investigation of CHIR-124 via conditional knockdown experiments confirmed that P. falciparum Aurora-related kinase 1 ( Pf Ark1) is implicated in its parasiticidal activity. Notably, CHIR-124 also inhibits β-hematin (synthetic hemozoin) formation and causes a dose-dependent increase in free heme that correlates with inhibition of parasite growth. These findings suggest that polypharmacology is involved in the activity of CHIR-124 against P. falciparum via the dual inhibition of Plasmodium Pf Ark1 and hemozoin formation, both essential for parasite proliferation. This is further supported by in vitro drug combination experiments, morphological studies, and resistance generation attempts. This study validates the feasibility of dual Plasmodium kinase/hemozoin formation inhibitors active against resistant strains with decreased resistance risks in the fight against malaria.

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Journal
ACS Chemical Biology
Published
2026-06-13
DOI
https://doi.org/10.1021/acschembio.6c00264
Primary Topic
Malaria Research and Control
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article
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article

The Human Chk1 Inhibitor CHIR-124 Shows Multistage Activity against the Human Malaria Parasite Plasmodium falciparum via Polypharmacological Inhibition of Pf Ark1 and Hemozoin Formation

John G. Woodland, M C Lee, María José Lafuente-Monasterio, Francisco‐Javier Gamo et al.
ACS Chemical Biology
Malaria Research and Control
article

The Human Chk1 Inhibitor CHIR-124 Shows Multistage Activity against the Human Malaria Parasite Plasmodium falciparum via Polypharmacological Inhibition of Pf Ark1 and Hemozoin Formation

John G. Woodland, M C Lee, María José Lafuente-Monasterio, Francisco‐Javier Gamo, Sergio Wittlin, Dale Taylor, Henrico Langeveld, Arne Alder, Janette Reader, Lauren B. Coulson, Jacquin C. Niles, Christian Scheurer, Dina Coertzen, Tim‐Wolf Gilberger, Kelly Chibale, Kathryn J. Wicht, David A. Fidock, Mariana Laureano de Souza, Lyn‐Marié Birkholtz, Jessica L. Bridgford, Sonja Ghidelli‐Disse, Jair L. Siqueira-Neto, Mariëtte van der Watt, Elizabeth A. Winzeler, Charisse Flerida A. Pasaje, Till S. Voss, Rachael Coyle, Luiz C. Godoy, Gareth Girling, Larnelle F. Garnie
article en

Abstract

High Resolution Image Download MS PowerPoint Slide The high burden of malaria and growing resistance to frontline antimalarials demand new drug target combinations with reduced propensities for conferring parasite resistance. An attractive approach for circumventing antimalarial drug resistance is target repurposing, in which known drugs that act through protein targets of human origin that are also active against the human malaria parasite Plasmodium falciparum are exploited to identify novel antimalarial drug targets. Here, we show that the human checkpoint kinase 1 (Chk1) inhibitor CHIR-124 is active in vitro against both drug-sensitive and drug-resistant asexual blood stage parasites and competitively binds to several Plasmodium kinases. The compound also shows moderate activity against both the liver and gametocyte forms of the parasite. Further target investigation of CHIR-124 via conditional knockdown experiments confirmed that P. falciparum Aurora-related kinase 1 ( Pf Ark1) is implicated in its parasiticidal activity. Notably, CHIR-124 also inhibits β-hematin (synthetic hemozoin) formation and causes a dose-dependent increase in free heme that correlates with inhibition of parasite growth. These findings suggest that polypharmacology is involved in the activity of CHIR-124 against P. falciparum via the dual inhibition of Plasmodium Pf Ark1 and hemozoin formation, both essential for parasite proliferation. This is further supported by in vitro drug combination experiments, morphological studies, and resistance generation attempts. This study validates the feasibility of dual Plasmodium kinase/hemozoin formation inhibitors active against resistant strains with decreased resistance risks in the fight against malaria.

ACS Chemical Biology
South African Medical Research Council (ZA), University of Cape Town (ZA), Swiss Tropical and Public Health Institute (CH), Universität Hamburg (DE), University of Dundee (GB), University of Basel (CH), Stellenbosch University (ZA), Columbia University Irving Medical Center (US), Discovery Centre (CA), Wellcome Sanger Institute (GB), University of California San Diego (US), GlaxoSmithKline (France) (FR), Wellcome Centre for Anti-Infectives Research (GB), CNR de la Résistance aux Antibiotiques (FR), Institute for Sustainable Development (ET), Centre for Structural Systems Biology (DE), Institute of Parasitology (CZ), Immunomedics (Germany) (DE), Massachusetts Institute of Technology (US), University of Montana (US), University of Pretoria (ZA), Bernhard Nocht Institute for Tropical Medicine (DE)
Good health and well-being
Openalex Percentile: Top 5%
Malaria Research and Control
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