Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer.

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.

• Authors: Jinmei Jin, Yaping Wu, Zeng Zhao, Ye Wu, Yu-Dong Zhou, Sanhong Liu, Qingyan Sun, Guizhu Yang, Jiayi Lin, Dale G Nagle, Jiangjiang Qin, Zhiyuan Zhang, Hong-Zhuan Chen, Weidong Zhang, Shuyang Sun, Xin Luan
• Journal: JCI insight (JCI Insight) Vol. 7 Issue 22 (11 22 2022) ISSN: 2379-3708 [Electronic] United States
• PMID: 36509291 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ubiquitin-Protein Ligases
• STAT3 protein, human
• STAT3 Transcription Factor

Topics

• Humans
• Proteolysis
• Squamous Cell Carcinoma of Head and Neck (drug therapy)
• Ubiquitin-Protein Ligases (metabolism)
• Head and Neck Neoplasms (drug therapy)
• STAT3 Transcription Factor (metabolism)