Pentacyclic triterpenoid-isothiocyanate derivatives target mutant p53 through dual mechanisms of reactivation and degradation

Mutations in the p53 tumor suppressor gene are common in human cancers, making mutant p53 an important therapeutic target. Here, we designed and evaluated a series of pentacyclic triterpenoid-isothiocyanate derivatives and identified compound 6a as a potent candidate with significant antitumor activity. Mechanistic studies demonstrated that 6a restores wild-type p53 conformation and transcriptional activity, leading to cell cycle arrest and apoptosis. Furthermore, 6a facilitates mutant p53 degradation through HSF-1 activation, upregulation of heat shock proteins (Hsp70 and Hsp90), and CHIP-mediated ubiquitination, driving proteasomal degradation. Molecular docking confirmed its specific binding to the DNA-binding domain of mutant p53 R175H. These findings establish compound 6a as a promising dual-function agent for targeting mutant p53, providing a new therapeutic strategy for cancers with p53 mutations.