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COTI\u20102, a thiosemicarbazone with orphan\u2010drug status for ovarian cancer, has proven an effective cytotoxic agent against various cancer cell lines\n                    <jats:italic>in vitro<\/jats:italic>\n                    , exhibited efficacy\n                    <jats:italic>in vivo<\/jats:italic>\n                    , and has demonstrated a good safety profile in Phase 1b human clinical trials. The proposed mechanism, direct engagement and refolding of mutant p53, has been supported by a combination of cell\u2010based assays and transcriptomics data. Through a combination of experimental and computational approaches, we demonstrate that this is an unlikely mechanism of action, and that\n                    <jats:bold>COTI<\/jats:bold>\n                    \u20102 instead likely acts as a selective, well\u2010tolerated, zinc chaperone to replace zinc ions lost to p53 mutants' deficient zinc\u2010binding.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70350","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T07:04:23Z","timestamp":1783580663000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Tale of Two Mechanisms: The p53 Modulator COTI\u20102 Is a Zn Metallochaperone"],"prefix":"10.1002","volume":"87","author":[{"given":"\u0130rem","family":"\u015eim\u015fek","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Windsor Windsor Ontario 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