发现新型 PROTAC SIRT6 降解剂，对肝细胞癌具有强大疗效

IF 5.3 2区材料科学 Q2 MATERIALS SCIENCE, MULTIDISCIPLINARY

ACS Applied Nano Materials 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

ACS Applied Nano Materials Multiple-

CiteScore

8.30

自引率

3.40%

发文量

1601

期刊介绍： ACS Applied Nano Materials is an interdisciplinary journal publishing original research covering all aspects of engineering, chemistry, physics and biology relevant to applications of nanomaterials. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important applications of nanomaterials.