Citation: Dandan Wang, Xiaoyu Ma, Yijin Zhao, Wenting Zou, Hua Wang, Yang Gao, Shimeng Wan, Jian Ni, Lilan Xin, Hai-Bing Zhou, Hongbing Cai, Chune Dong. The discovery of acyl thiourea derivatives as potent hydrophobic tagging degraders targeting SIRT2 for the treatment of ovarian cancer[J]. Chinese Chemical Letters, ;2026, 37(4): 111143. doi: 10.1016/j.cclet.2025.111143 shu

The discovery of acyl thiourea derivatives as potent hydrophobic tagging degraders targeting SIRT2 for the treatment of ovarian cancer

Dandan Wang ^{a, c, 1} ,
Xiaoyu Ma ^{a, b, 1} ,
Yijin Zhao ^{a, c, 1} ,
Wenting Zou ^{a, b} ,
Hua Wang ^{a, c} ,
Yang Gao ^{a, c} ,
Shimeng Wan ^{a, c} ,
Jian Ni ^{a, b} ,
Lilan Xin ^{a, b} ,
Hai-Bing Zhou ^{a, b} ,
Hongbing Cai ^{a, c, *,} ,
Chune Dong ^{a, b, *,}

a.
Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
b.
State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University, Wuhan 430071, China
c.
Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan 430071, China

chb2105@163.com

cdong@whu.edu.cn

Received Date: 11 December 2024
Revised Date: 25 March 2025
Accepted Date: 26 March 2025
Available Online: 26 March 2025

Figures(2)

Sirtuin 2 (SIRT2) is one of the key members of sirtuins family that plays important role in regulating many physiological processes. Recent evidences have revealed that SIRT2 is associated with the development, progression and metastasis of ovarian cancer. In this study, guided by an in-depth analysis of the clinical characteristics of the expression pattern of SIRT2 in ovarian cancer patients, the first SIRT2-targeted hydrophobic tagging (HyT) degraders have been developed. These acyl thiourea degraders exhibited remarkable anti-proliferative activity in several ovarian cancer cells. Among them, the most effective compound Ⅱ-6 exhibited excellent anti-tumor activity both in vitro and in vivo (half maximal inhibitory concentration (IC₅₀) = 0.002 ± 0.001 µmol/L). In addition, Ⅱ-6 was found to effectively suppress cancer cell proliferation and migration, as well as cell cycle arrest and apoptosis. Moreover, further investigation revealed that compound Ⅱ-6 indirectly induced DNA damage through the H4K20me2/53BP1 pathway by degradation of SIRT2. The study not only exemplifies the advantage of the novel HyT degradation strategy but also prove the great potential of SIRT2 as a promising target for drug development of ovarian cancer.
- Ovarian cancer,
- Hydrophobic tagging degraders,
- Sirtuin 2,
- Acyl thioureas,
- Anti-tumor activity,
- Degradation
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