五环三萜-异硫氰酸酯衍生物双重机制靶向突变p53研究

Abstract

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.