Design, synthesis, and biological characterization of a potent STAT3 degrader for the treatment of gastric cancer

被引:12
|
作者
Li, Haobin [1 ,2 ]
Wang, Lingling [1 ,3 ]
Cao, Fei [1 ,4 ]
Yu, Dehua [1 ]
Yang, Jing [1 ]
Yu, Xuefei [1 ]
Dong, Jinyun [1 ,5 ]
Qin, Jiang-Jiang [1 ,5 ]
Guan, Xiaoqing [1 ,5 ]
机构
[1] Chinese Acad Sci, Canc Hosp, Zhejiang Canc Hosp, Inst Basic Med & Canc IBMC,Univ Chinese Acad Sci, Hangzhou, Peoples R China
[2] Zhejiang Chinese Med Univ, Sch Pharmaceut Sci, Hangzhou, Peoples R China
[3] Tianjin Univ, Sch Life Sci, Tianjin, Peoples R China
[4] Zhejiang Univ Technol, Coll Pharmaceut Sci, Hangzhou, Peoples R China
[5] Key Lab Prevent Diag & Therapy Upper Gastrointesti, Hangzhou, Peoples R China
关键词
stat3; gastric cancer; S3I-201; protac; degradation; INHIBITOR; BURDEN; LIGASE; CELLS;
D O I
10.3389/fphar.2022.944455
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Gastric cancer is a common malignant tumor that threatens human health, and its occurrence and development mechanism is a complex process involving multiple genes and multiple signals. Signal transducer and activator of transcription 3 (STAT3) has been elucidated as a promising target for developing anticancer drugs in gastric cancer. However, there is no FDA-approved STAT3 inhibitor yet. Herein, we report the design and synthesis of a class of STAT3 degraders based on proteolysis-targeting chimeras (PROTACs). We first synthesized an analog of the STAT3 inhibitor S3I-201 as a ligand, using the cereblon (CRBN)/cullin 4A E3 ligase ligand pomalidomide to synthesize a series of PROTACs. Among them, the SDL-1 achieves the degradation of STAT3 protein in vitro, and exhibits good anti-gastric cancer cell proliferation activity, inhibits invasion and metastasis of MKN1 cell, and induces MKN1 cell apoptosis and arrests cell cycle at the same time. Our study shows that SDL-1 is a potent STAT3 degrader and may serve as a potential anti-gastric cancer drug, providing ideas for further development of drugs for clinical use.
引用
收藏
页数:12
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