Activating p53 ^Y220C with a Mutant-Specific Small Molecule

TP53 is the most commonly mutated gene in cancer, but it remains recalcitrant to clinically meaningful therapeutic reactivation. We present here the discovery and characterization of a small molecule chemical inducer of proximity that activates mutant p53. We named this compound TR anscriptional A ctivator of p 53 ( TRAP-1 ) due to its ability to engage mutant p53 and BRD4 in a ternary complex, which potently activates mutant p53 and triggers robust p53 target gene transcription. Treatment of p53 ^Y220C expressing pancreatic cell lines with TRAP-1 results in rapid upregulation of p21 and other p53 target genes and inhibits the growth of p53 ^Y220C -expressing cell lines. Negative control compounds that are unable to form a ternary complex do not have these effects, demonstrating the necessity of chemically induced proximity for the observed pharmacology. This approach to activating mutant p53 highlights how chemically induced proximity can be used to restore the functions of tumor suppressor proteins that have been inactivated by mutation in cancer.