Discovery of a potent and selective PROTAC degrader for STAT3†

Abstract

The signal transducer and activator of transcription 3 (STAT3) protein and the p53 protein play opposite roles in the regulation of cell pathways. Activation of STAT3 upregulates survival pathways, while activation of p53 triggers apoptosis pathways. Therefore, STAT3 inhibition of p53 expression may play a central role in tumor development, and targeting STAT3 represents a promising therapeutic method for p53 reactivation in many cancers. Here, we report the design of S3D5, a BP-1-102-based proteolysis targeting chimera (PROTAC) that induces time- and dose-dependent degradation of STAT3 in HepG2 cells without significant effects on other STAT proteins. Preliminary mechanism studies show that S3D5 degradation of the STAT3 protein is mediated by the ubiquitin–proteasome system (UPS). S3D5 exhibits good anti-hepatocellular carcinoma cell proliferation activity, which can be explained by activating the p53 pathway. These findings demonstrate the utility and importance of PROTACs as preliminary chemical tools to investigate the function of the STAT3 protein. Further, S3D5 may serve as a potential anti-hepatocellular carcinoma agent, laying a practical foundation for further development of potent STAT3-targeting PROTACs.