Discovery of Novel PROTAC SIRT6 Degraders with Potent Efficacy against Hepatocellular Carcinoma
Jinbo Huang, Jiajie Su, Haiyu Wang, Jiayi Chen, Yuan Tian, Jun Zhang, Tingting Feng, Longjiang Di, Xiaopeng Lu, Hao Sheng, Qian Zhu, Xinyun Chen, J. Wang, Xingkai He, Yerkezhan Yerkinkazhina, Zhongyi Xie, Yuxin Shu, Tian‐Shu Kang, Huangqi Tang, Jinqin Qian, Wei‐Guo Zhu
Abstract
Sirtuin 6 (SIRT6), a member of the SIRT family, plays essential roles in the regulation of metabolism, inflammation, aging, DNA repair, and cancer development, making it a promising anticancer drug target. Herein, we present our use of proteolysis-targeting chimera (PROTAC) technology to formulate a series of highly potent and selective SIRT6 degraders. One of the degraders, SZU-B6, induced the near-complete degradation of SIRT6 in both SK-HEP-1 and Huh-7 cell lines and more potently inhibited hepatocellular carcinoma (HCC) cell proliferation than the parental inhibitors. In preliminary mechanistic studies, SZU-B6 hampered DNA damage repair, promoting the cellular radiosensitization of cancer cells. Our SIRT6 degrader SZU-B6 displayed promising antitumor activity, particularly when combined with the well-known kinase inhibitor sorafenib or irradiation in an SK-HEP-1 xenograft mouse model. Our results suggest that these PROTACs might constitute a potent therapeutic strategy for HCC.