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

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.

S3I-201; degradation; gastric cancer; protac; stat3.