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Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer
Jinmei Jin, … , Shuyang Sun, Xin Luan
Jinmei Jin, … , Shuyang Sun, Xin Luan
Published November 22, 2022
Citation Information: JCI Insight. 2022;7(22):e160606. https://doi.org/10.1172/jci.insight.160606.
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Research Article Oncology Therapeutics

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

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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

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Figure 1

Expression of STAT3 and its clinical significance.

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Expression of STAT3 and its clinical significance.
(A and D) STAT3 expre...
(A and D) STAT3 expression was significantly increased in patients with HNSCC (GSE30784 database). (B and E) STAT3 expression was increased in patients with CRC according to the GSE21815 database. (C, F, and G) Increased expression of STAT3 protein was observed in biopsy samples from patients with HNSCC and patients with CRC (n = 3 patients). ***P < 0.001 when compared with the control group. P values are from 2-tailed paired t tests (D–G).

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