A tale of two mechanisms: The p53 modulator COTI-2 is a Zn metallochaperone

Mutations in, or misregulation of, Tp53 are found in approximately 50% of all cancers. p53 functions by ensuring that cells with irretrievably damaged DNA undergo apoptosis. When p53 is non-functional in cells that may also be undergoing uncontrolled cell growth (due to other mutations), cancer readily emerges. Consequently, restoring the function of misregulated and mutated Tp53 is an incredibly important goal in therapeutic oncology. Tp53 mutations often induce conformational changes that inhibit the protein’s ability to engage its DNA response element. Small molecule chaperones could theoretically restore the proper shape and activity, but this is a far more challenging design problem than the typical paradigm of designing inhibitors of protein function. Consequently, it is unsurprising that there are no approved p53-targeting drugs. COTI-2, a thiosemicarbazone with orphan-drug status for ovarian cancer, has proven an effective cytotoxic agent against various cancer cell lines in vitro, exhibited efficacy in vivo, 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-based assays and transcriptomics data. We propose that this is an unlikely mechanism of action, and that instead COTI-2 is acting as a selective, well-tolerated, zinc chaperone to replace zinc ions lost to p53 mutants’ deficient zinc-binding. We discuss that COTI-2 likely also works through other mechanisms but demonstrate that zinc-binding is necessary for the exceptional bioactivity. The promising therapeutic potential of this molecule and additional evidence for its zinc chaperone activity is discussed. This would make it the first well-tolerated zinc chaperone with pharmacological implications not only for cancer but for other zinc deficiency-related diseases.