Cancer cells experience elevated oxidative stress and rely on MutT Homologue 1 (MTH1) to sanitize the oxidized nucleotide pool and prevent the incorporation of damaged nucleotides into DNA. This dependency has established MTH1 as a promising target for anticancer drug development. Here, we identify acoramidis─an approved therapeutic for transthyretin amyloidosis─as a previously unrecognized and selective inhibitor of MTH1 through a drug-repositioning strategy. Biochemical analyses demonstrate that acoramidis competitively inhibits MTH1 enzymatic activity with micromolar potency. Thermodynamic measurements reveal that acoramidis binding is characterized by substantial entropic favorability, suggesting a dominant contribution from hydrophobic interactions and conformational adaptability. X-ray crystallography uncovers a ligand-induced expansion of the substrate-binding pocket caused by displacement of the gatekeeper residue Phe27, a structural alteration not observed in the TH287-bound or apo forms. Among the key interactions in the MTH1 active site, hydrogen bonding with residues Asp119 and Asp120 plays a central role in ligand recognition and is also exploited by known inhibitors. However, the pronounced conformational rearrangement induced by acoramidis is unique and likely underlies its distinct thermodynamic signature and moderate binding affinity. Given its well-established clinical safety and pharmacokinetic properties, acoramidis provides an immediately accessible chemical scaffold for further optimization. Overall, this study identifies a clinically approved drug with a novel mechanism of MTH1 inhibition and establishes a foundation for the rational design of next-generation MTH1 inhibitors with improved potency and potential anticancer efficacy.
Yokoyama et al. (Tue,) studied this question.