Mechanism-based peroxiredoxin 3 inhibitors exploit a covalent warhead for cancer therapy.

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,

SUBMITTER: Nelson KJ 

PROVIDER: S-EPMC12577686 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature