Discovery of Novel PROTAC SIRT6 Degraders with Potent Efficacy against Hepatocellular Carcinoma

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.