Wang Shumei, Li Zhenzhen, Ma Siyue, Zhang Shuxin, Guo Shuxian, Ma Zhao, Du Lupei, Li Minyong
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; College of Life Sciences, Northwest Normal University, Lanzhou, Gansu 730070, China.
Bioorg Chem. 2024 Dec;153:107801. doi: 10.1016/j.bioorg.2024.107801. Epub 2024 Sep 3.
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.
对硼替佐米等蛋白酶体抑制剂产生耐药性是多发性骨髓瘤（MM）治疗中的一项重大挑战。靶向蛋白降解嵌合体（PROTACs）是一种新兴的治疗方法，可诱导靶蛋白的选择性降解，为克服耐药性提供了一种有前景的解决方案。在本研究中，我们设计并合成了新型小分子PROTACs，其可诱导20S蛋白酶体亚基β5降解，作为克服硼替佐米耐药性的一种策略。这些20S蛋白酶体亚基β5 PROTACs对20S蛋白酶体亚基β5和脑啡肽（CRBN）表现出相当高的结合亲和力，有效诱导20S蛋白酶体亚基β5降解，并对一组癌细胞系表现出强大的抗增殖活性。值得注意的是，PROTACs 12f和14在体外和体内对咽癌细胞系FaDu和硼替佐米耐药的MM细胞系KM3/BTZ均表现出强大的抗肿瘤作用，且安全性良好。综上所述，我们的研究结果突出了PROTACs 12f和14作为新型20S蛋白酶体亚基β5降解剂治疗咽癌和克服MM中硼替佐米耐药性的潜力。
