Faculty and Student Publications
Document Type
Article
Publication Date
11-22-2022
Abstract
The aberrant activation of STAT3 is associated with the etiology and progression in a variety of malignant epithelial-derived tumors, including head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC). Due to the lack of an enzymatic catalytic site or a ligand-binding pocket, there are no small-molecule inhibitors directly targeting STAT3 that have been approved for clinical translation. Emerging proteolysis targeting chimeric (PROTAC) technology-based approach represents a potential strategy to overcome the limitations of conventional inhibitors and inhibit activation of STAT3 and downstream genes. In this study, the heterobifunctional small-molecule-based PROTACs are successfully prepared from toosendanin (TSN), with 1 portion binding to STAT3 and the other portion binding to an E3 ubiquitin ligase. The optimized lead PROTAC (TSM-1) exhibits superior selectivity, potency, and robust antitumor effects in STAT3-dependent HNSCC and CRC - especially in clinically relevant patient-derived xenografts (PDX) and patient-derived organoids (PDO). The following mechanistic investigation identifies the reduced expression of critical downstream STAT3 effectors, through which TSM-1 promotes cell cycle arrest and apoptosis in tumor cells. These findings provide the first demonstration to our knowledge of a successful PROTAC-targeting strategy in STAT3-dependent epithelial cancer.
Relational Format
journal article
Recommended Citation
Jin, J., Wu, Y., Zhao, Z., Wu, Y., Zhou, Y., Liu, S., Sun, Q., Yang, G., Lin, J., Nagle, D. G., Qin, J., Zhang, Z., Chen, H., Zhang, W., Sun, S., & Luan, X. (2022). Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer. JCI Insight, 7(22), e160606. https://doi.org/10.1172/jci.insight.160606
DOI
10.1172/jci.insight.160606
Accessibility Status
Searchable text