ArticleScience advances2025
Mechanism-based peroxiredoxin 3 inhibitors exploit a covalent warhead for cancer therapy.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Experimental workflows for the accurate identification of mitochondrial redox events.Redox biology · 2026Review
- Preclinical characterization and phase 1 clinical testing of targeting mitochondrial peroxiredoxin 3 in cancer.Nature communications · 2026Article
- Review
- ALDH1L2 induces resistance to chemotherapy in small cell lung cancer by inhibiting ferroptosis.Redox biology · 2026Article
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Authors and funding
12 authors.
Funding
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Abstract
Covalent inhibitors that are approved and marketed drugs exploit a wide array of warheads and reactions with amino acid side chain-based nucleophiles. Thiostrepton (TS) inhibits the peroxidase activity of the mitochondrial antioxidant protein peroxiredoxin 3 by forming a covalent crosslink between the two active site cysteine residues. Peroxiredoxin 3 inactivation increases reactive oxygen species levels, induces cancer cell death in preclinical models, and shows promise in an ongoing clinical trial for malignant mesothelioma using direct pleural infusion. We report the identification of the minimal fragment of TS that contains tandem dehydro-alanine (DHA) moieties and maintains anticancer activity while losing interactions with three alternative targets of intact TS. Biochemical, kinetic, cellular, and structural studies demonstrate that this fragment is a mechanism-based peroxiredoxin inhibitor. These findings represent a promising start toward a pro-oxidant approach for cancer therapy. Moreover, the data support that the DHA moiety should be added to the covalent warhead arsenal.
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