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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 7

TSM-1 decreased STAT3 protein levels and inhibited tumor growth in vivo.

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TSM-1 decreased STAT3 protein levels and inhibited tumor growth in vivo....
(A, E, and I) The treatment regimen diagrams (n = 5 mice). (B, C, F, G, J, and K) Both tumor volume (B, F, and J) and body weight (C, G, and K) were monitored every 2 days. (A, D, E, H, I, and L) When mice were sacrificed, the tumors were photographed (A, E, and I), and tumor weight was recorded (D, H, and L). (M–R) Western blot analyses show that TSM-1 treatment inhibited STAT3 and its downstream signaling pathway–related target gene expression in vivo. *P < 0.05, **P < 0.01, and ***P < 0.001 when compared with the control group. P values are from ordinary one-way ANOVA with Dunnett’s multiple-comparison test (D, H, and L) or 2-way ANOVA with Tukey’s multiple-comparison test (B, F, J, P, Q, and R).

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ISSN 2379-3708

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