期刊
FRONTIERS IN PHARMACOLOGY
卷 13, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2022.944455
关键词
stat3; gastric cancer; S3I-201; protac; degradation
资金
- Program of Zhejiang Provincial TCM Scitech Plan
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province [2020ZZ005]
- [2022E10021]
The study reports the design and synthesis of a class of STAT3 degraders based on proteolysis-targeting chimeras (PROTACs). The SDL-1 compound achieved degradation of STAT3 protein in vitro and exhibited good anti-gastric cancer cell proliferation activity, as well as inhibiting invasion and metastasis.
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.
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