Discovery of novel 20S proteasome subunit β5 PROTAC degraders as potential therapeutics for pharyngeal carcinoma and Bortezomib-resistant multiple myeloma.

Resistance to proteasome inhibitors like Bortezomib is a major challenge in the treatment of multiple myeloma (MM). Proteolysis targeting chimeras (PROTACs), an emerging therapeutic approach that induces selective degradation of target proteins, offer a promising solution to overcome drug resistance. In this study, we designed and synthesized novel small-molecule PROTACs that induce 20S proteasome subunit β5 degradation as a strategy to overcome Bortezomib resistance. These 20S proteasome subunit β5 PROTACs demonstrated considerable binding affinity to 20S proteasome subunit β5 and cereblon (CRBN), effectively induced 20S proteasome subunit β5 degradation, and exhibited potent antiproliferative activity against a panel of cancer cell lines. Notably, PROTACs 12f and 14 displayed robust antitumor effects against both the pharyngeal carcinoma cell line FaDu and the Bortezomib-resistant MM cell line KM3/BTZ in vitro and in vivo with excellent safety profiles. Taken together, our findings highlight the potential of PROTACs 12f and 14 as novel 20S proteasome subunit β5-degrading agents for the treatment of pharyngeal carcinoma and overcoming Bortezomib resistance in MM.