ArticleCell chemical biology2025
Plasmodiumfalciparum protein kinase 6 and hemozoin formation are inhibited by a type II human kinase inhibitor exhibiting antimalarial activity.
Article in Cell chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Cell cycle checkpoint activity in the malaria parasitemSphere · 2026Article
- The Human Chk1 Inhibitor CHIR-124 Shows Multistage Activity against the Human Malaria ParasiteACS chemical biology · 2026Article
- Using Unbiased Chemical Proteomics Approaches to Explore the Target Landscape of the Resistance Refractory 7-Azaindole MMV022224 inACS infectious diseases · 2026Article
- Genome-Guided Discovery of Antimalarial 4-Amino-2,4-Pentadienoate-Containing Cyclolipodepsipeptides.Angewandte Chemie (International ed. in English) · 2026Article
- Article
- Norditerpene Natural Products from Subterranean Fungi with Anti-Parasitic Activity.Microorganisms · 2025Article
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Authors and funding
37 authors.
Funding
Abstract
Kinase inhibitors are potent therapeutics, but most essential Plasmodium kinases remain unexploited as antimalarial targets. We identified compound 12, a type II kinase inhibitor based on aminopyridine and 2,6-benzimidazole scaffolds, as a lead compound with nanomolar potency, fast action, and in vivo activity in the Plasmodium berghei rodent malaria model. Three-hybrid luciferase fragment complementation, enzymatic studies, and cellular thermal shift assays implicated Plasmodium protein kinase 6 (PfPK6) as the target. However, conditional knockdown of PfPK6 did not alter 12 potency, suggesting complex mechanisms of action. In vitro selection for compound 12 resistance revealed mutations in three transporters: multidrug-resistance protein 1, chloroquine resistance transporter and V-type ATPase, indicating a digestive vacuole site of action. Compound 12 inhibited β-hematin and hemozoin formation while increasing free heme levels, suggesting antimalarial activity via blockade of heme detoxification. Our studies repurpose a safe human kinase inhibitor as a potent, fast-acting antimalarial with established in vivo efficacy.
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Registered trials
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