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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 8

TSM-1 enhanced anti–PD-L1 immune checkpoint blockade.

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TSM-1 enhanced anti–PD-L1 immune checkpoint blockade.
(A) The pattern di...
(A) The pattern diagram. For the combinatorial immunotherapy, anti–PD-L1 antibody (12.5 μg per animal) was i.p. injected on days 1, 3, and 5 in addition to the vein injection of 2 mg/kg TSM-1. (B) When mice were sacrificed, the tumors were photographed (n = 5 mice). (C and D) Both tumor volume (C) and body weight (D) were monitored every day (n = 5 mice). (E) When mice were sacrificed, tumor weight was recorded (n = 5 mice). (F) TSM-1 led to decreased STAT3 and PD-L1 expression compared with control group. (G and H) Statistical analysis results are shown (n = 3 mice). *P < 0.01 and ***P < 0.001 versus the control group. P values are from ordinary 1-way ANOVA with Dunnett’s multiple-comparison test (E, G, and H) or 2-way ANOVA with Tukey’s multiple-comparison test (C).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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