Repurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations

The tumor suppressor p53 is inactivated by over hundreds of heterogenous mutations in cancer. Here, we purposefully selected phenotypically reversible temperature-sensitive (TS) p53 mutations for pharmacological rescue with thermostability as the compound-screening readout. This rational screening identified antiparasitic drug potassium antimony tartrate (PAT) as an agent that can thermostabilize the representative TS mutant p53-V272M via noncovalent binding. PAT met the three basic criteria for a targeted drug: availability of a co-crystal structure, compatible structure-activity relationship, and intracellular target specificity, consequently exhibiting antitumor activity in a xenograft mouse model. At the antimony dose in clinical antiparasitic therapy, PAT effectively and specifically rescued p53-V272M in patient-derived primary leukemia cells in single-cell RNA sequencing. Further scanning of 815 frequent p53-missense mutations identified 65 potential PAT-treatable mutations, most of which were temperature sensitive. These results lay the groundwork for repurposing noncovalent antiparasitic antimonials for precisely treating cancers with the 65 p53 mutations. [Display omitted] •Rationally identify PAT as a noncovalent mutant p53 rescue compound•PAT meets the three go-to criteria evaluating a first-in-class targeted compound•PAT rescues p53-V272M in patient-derived primary cancer cells at the clinical dose•65 temperature-sensitive p53 mutants can be rescued by PAT Tang et al. reported that the antiparasitic PAT noncovalently reactivated 65 temperature-sensitive p53 mutants. PAT met the three go-to criteria evaluating a targeted compound and effectively rescued mutant p53 in patient-derived cancer cells at the clinical dose and thus has practical repurposing potential.