2. Academic Validation
  3. Discovery of Novel PROTAC SIRT6 Degraders with Potent Efficacy against Hepatocellular Carcinoma

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

  • J Med Chem. 2024 Oct 10;67(19):17319-17349. doi: 10.1021/acs.jmedchem.4c01223.
Jinbo Huang 1 2 3,  Jiajie Su 1 2,  Haiyu Wang 1 2,  Jiayi Chen 1 2,  Yuan Tian 1 2,  Jun Zhang 1 2,  Tingting Feng 1,  Longjiang Di 4,  Xiaopeng Lu 1 2,  Hao Sheng 1,  Qian Zhu 1 2,  Xinyun Chen 1,  Jingchao Wang 1,  Xingkai He 1,  Yerkezhan Yerkinkazhina 1,  Zhongyi Xie 1,  Yuxin Shu 1 5,  Tianshu Kang 1,  Huangqi Tang 1,  Jinqin Qian 6,  Wei-Guo Zhu 1 2 5
Affiliations

Affiliations

  • 1 International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Health Science Centre School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China.
  • 2 Shenzhen University School of Pharmacy, Shenzhen University Medical School, Shenzhen 518055, China.
  • 3 National Engineering Research Centrer for Biotechnology, Shenzhen 518055, China.
  • 4 School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 5 School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui 241002, China.
  • 6 Department of Urology, Peking University First Hospital, Beijing 100035, China.
PMID: 39323022 DOI: 10.1021/acs.jmedchem.4c01223
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.

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