硼替佐米
蛋白酶体
多发性骨髓瘤
蛋白质亚单位
蛋白酶体抑制剂
化学
癌症研究
蛋白质降解
药理学
生物
生物化学
免疫学
基因
作者
Shumei Wang,Zhenzhen Li,Siyue Ma,Shuxin Zhang,Shuxian Guo,Zhao Ma,Lüpei Du,Minyong Li
标识
DOI:10.1016/j.bioorg.2024.107801
摘要
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.
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