发现新型 PROTAC SIRT6 降解剂，对肝细胞癌具有强大疗效

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-09-25 DOI:10.1021/acs.jmedchem.4c01223

Jinbo Huang, Jiajie Su, Haiyu Wang, Jiayi Chen, Yuan Tian, Jun Zhang, Tingting Feng, Longjiang Di, Xiaopeng Lu, Hao Sheng, Qian Zhu, Xinyun Chen, Jingchao Wang, Xingkai He, Yerkezhan Yerkinkazhina, Zhongyi Xie, Yuxin Shu, Tianshu Kang, Huangqi Tang, Jinqin Qian, Wei-Guo Zhu

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引用次数: 0

摘要

Sirtuin 6（SIRT6）是 SIRT 家族的成员之一，在调节新陈代谢、炎症、衰老、DNA 修复和癌症发展方面发挥着重要作用，因此是一个很有前景的抗癌药物靶点。在此，我们介绍了利用蛋白水解靶向嵌合体（PROTAC）技术配制出的一系列高效力、高选择性 SIRT6 降解剂。其中一种降解剂 SZU-B6 能诱导 SK-HEP-1 和 Huh-7 细胞系中的 SIRT6 几乎完全降解，并且比亲代抑制剂更有效地抑制肝细胞癌（HCC）细胞增殖。在初步机理研究中，SZU-B6 阻碍了 DNA 损伤修复，促进了癌细胞的细胞放射敏化。我们的SIRT6降解剂SZU-B6显示出了良好的抗肿瘤活性，尤其是在SK-HEP-1异种移植小鼠模型中与著名的激酶抑制剂索拉非尼或辐照联合使用时。我们的研究结果表明，这些 PROTACs 可能是治疗 HCC 的有效策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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

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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.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.