UC Irvine

The tumor suppressor p53 plays a crucial role in preventing cancer initiation and progression by inducing cell cycle arrest and apoptosis. Mutations in p53 are common in cancers, leading to its inactivation and subsequent tumor growth. This thesis focuses on the second generation of compounds targeting the L1/S3 pocket for p53 reactivation, with a brief overview of the first-generation compounds. The first generation includes compounds like UCI-LC0023 and UCI-LC0019, which bind noncovalently to stabilize and reactivate mutant p53, thereby restoring its tumor-suppressing functions. The second generation features pyrimidine trione derivatives such as UCI-1001 and its analogs UCI-1014, which have shown promise in correcting mutant p53 and restoring wild-type-like activities in cancer cells. Several methodologies were used to study these compounds, including molecular dynamics simulations, virtual screening, cell viability assays, IC50 determination, and immunoblotting. Additionally, techniques such as immunofluorescence, flow cytometry, differential scanning fluorimetry, real-time RT-PCR, RNA sequencing, and chromatin immunoprecipitation were utilized to elucidate the mechanisms of action for the UCI-1001 series. The investigation revealed that UCI-1001 and its analogs significantly reactivated mutant p53, demonstrating considerable potential as therapeutic interventions for p53-mutant cancers. These findings underscore the promise of developing new treatments targeting p53 mutations, highlighting the feasibility of these compounds in preclinical models and opening new pathways for precision oncology aimed at restoring p53 function in tumor cells.