Discovery of\nNovel PROTAC SIRT6 Degraders with Potent\nEfficacy against Hepatocellular Carcinoma

Sirtuin 6 (SIRT6), a member of the SIRT family, plays\nessential\nroles in the regulation of metabolism, inflammation, aging, DNA repair,\nand cancer development, making it a promising anticancer drug target.\nHerein, we present our use of proteolysis-targeting chimera (PROTAC)\ntechnology to formulate a series of highly potent and selective SIRT6\ndegraders. One of the degraders, <b>SZU-B6</b>, induced the\nnear-complete degradation of SIRT6 in both SK-HEP-1 and Huh-7 cell\nlines and more potently inhibited hepatocellular carcinoma (HCC) cell\nproliferation than the parental inhibitors. In preliminary mechanistic\nstudies, <b>SZU-B6</b> hampered DNA damage repair, promoting\nthe cellular radiosensitization of cancer cells. Our SIRT6 degrader <b>SZU-B6</b> displayed promising antitumor activity, particularly\nwhen combined with the well-known kinase inhibitor sorafenib or irradiation\nin an SK-HEP-1 xenograft mouse model. Our results suggest that these\nPROTACs might constitute a potent therapeutic strategy for HCC.