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作者

Dandan Wang Yihe Wu Yijin Zhao Xiaoyu Ma Jiahao Shi Jian Ni Yang Gao Hongbing Cai Chune Dong Hai-Bing Zhou

作者单位

⁴Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China ²Department of Gynecological Oncology, The Affiliated Cancer Hospital of Shandong First Medical University, Jinan, 250117, China ⁵State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, Provincial Key Laboratory of Developmentally Originated Disease, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals,School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China ³The authors contributed equally to this work. ¹Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China

刊名

European Journal of Medicinal Chemistry

年份

2025

页码

118295

ISSN

0223-5234

摘要

Ovarian cancer is a highly lethal gynecological malignancy that poses a significant threat to women's health. Current treatments for patients with clinical recurrence and drug resistance are limited, underscoring the urgent need for new therapeutic strategies. SIRT2, one subtype of sirtuin protein family, has been shown to promote tumor cell proliferation, migration, and invasion by regulating multiple signaling pathways through deacetylation. In this study, we discovered that knockdown of SIRT2...更多

Ovarian cancer is a highly lethal gynecological malignancy that poses a significant threat to women's health. Current treatments for patients with clinical recurrence and drug resistance are limited, underscoring the urgent need for new therapeutic strategies. SIRT2, one subtype of sirtuin protein family, has been shown to promote tumor cell proliferation, migration, and invasion by regulating multiple signaling pathways through deacetylation. In this study, we discovered that knockdown of SIRT2 significantly inhibited the migration and invasion of ovarian cancer cells. To develop targeted therapies, we designed and synthesized a series of SIRT2-targeted PROTACs based on the small molecule inhibitor Tenovin-6. These PROTACs exhibited potent SIRT2 degradation capability and significant anti-proliferative activity in several ovarian cancer cell lines. Among them, W10 demonstrated the most potent anti-proliferative activity both in vitro and in vivo, with an IC value of 0.08 ± 0.04 μmol/L and a selectivity index of 33.00. W10 significantly suppressed clonogenic formation and migration, induced cell cycle arrest, and promoted apoptosis. Mechanistically, W10 inhibited the AKT/mTOR signaling pathway by indirectly degrading SIRT2 and blocking downstream protein phosphorylation, thereby disrupting the signaling cascade and suppressing tumor development.收起

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