Promising Proteolysis-Targeting Chimera for Mutant p53-R175H.

Abstract

The tumor suppressor protein p53 is among the most commonly mutated proteins across a variety of cancer types. Notably, the p53 R175H mutation ranks as one of the most prevalent hotspot mutations. Proteolysis-targeting chimeras (PROTACs) represent a class of bifunctional molecules capable of harnessing the cellular ubiquitin-proteasome pathway to facilitate targeted protein degradation. Despite the potential of PROTACs, limited research has been directed toward the degradation of the p53-R175H mutant protein. In this study, we developed a series of peptide-based PROTACs, leveraging known peptide ligands for both the p53-R175H mutation and the E3 ubiquitin ligase VHL. Our findings indicate that one of these peptide-based PROTACs is capable of directing the p53-R175H protein to the proteasome for degradation within a recombinant expression system. Moreover, by synthesizing a fusion peptide PROTAC molecule that incorporates a membrane-penetrating peptide, we have demonstrated its ability to traverse cellular membranes and subsequently reduce the levels of the p53-R175H mutant protein. Importantly, the degradation of p53-R175H was found to mitigate the cellular migration and invasion. In summary, our study introduces a novel class of protein degraders and establishes a foundational framework for the therapeutic management of cancers associated with p53 mutations.