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, <b>SZU-B6</b>, 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, <b>SZU-B6</b> hampered DNA damage repair, promoting the cellular radiosensitization of cancer cells. Our SIRT6 degrader <b>SZU-B6</b> 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.
Authors
- Tian‐Shu Kang
- Jinqin Qian (ORCID: https://orcid.org/0000-0002-5549-5800)
- J. Wang
- Jinbo Huang (ORCID: https://orcid.org/0000-0002-2424-2018)
- Qian Zhu (ORCID: https://orcid.org/0000-0003-1045-8819)
- Xiaopeng Lu (ORCID: https://orcid.org/0000-0001-7746-5322)
- Yuan Tian (ORCID: https://orcid.org/0000-0001-6174-3359)
- Tingting Feng
- Wei‐Guo Zhu (ORCID: https://orcid.org/0000-0001-8385-6581)
- Longjiang Di (ORCID: https://orcid.org/0000-0003-4426-2216)
- Haiyu Wang (ORCID: https://orcid.org/0000-0002-2369-6026)
- Jun Zhang (ORCID: https://orcid.org/0000-0002-6523-7573)
- Jiayi Chen (ORCID: https://orcid.org/0000-0001-6417-290X)
- Hao Sheng (ORCID: https://orcid.org/0000-0002-2044-8764)
- Yuxin Shu (ORCID: https://orcid.org/0009-0006-1601-9138)
- Huangqi Tang (ORCID: https://orcid.org/0000-0003-3297-6545)
- Yerkezhan Yerkinkazhina
- Xinyun Chen
- Xingkai He
- Zhongyi Xie
- Jiajie Su
Institutions
- Wannan Medical College (CN)
- Shenzhen University (CN)
- Peking University (CN)
- Peking University First Hospital (CN)
- Shenzhen University Health Science Center (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-26
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01223
- Citations
- 28
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 6.55
Funders
- National Natural Science Foundation of China
- Guangdong Science and Technology Department
- Shenzhen University
- Science, Technology and Innovation Commission of Shenzhen Municipality
- Anhui Normal University
- National Key Research and Development Program of China
- Basic and Applied Basic Research Foundation of Guangdong Province