Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Oncology Therapeutics

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

  • Text
  • PDF
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

×

Figure 10

TSM-1 inhibited HNSCC tumor growth in PDX models.

Options: View larger image (or click on image) Download as PowerPoint
TSM-1 inhibited HNSCC tumor growth in PDX models.
(A) The treatment regi...
(A) The treatment regimen diagrams. (B–G) Both tumor volume (C and F) and body weight (B and E) were monitored every 2 days (n = 5 mice in B, and n = 7 mice in E); when mice were sacrificed, the tumors were photographed (B and E), and tumor weight was recorded (D and G). (H and I) Western blot analyses showed that TSM-1 treatment inhibited STAT3 and its downstream signaling pathway–related target gene expression in PDX SCC342 model. (J) TSM-1 treatment led to significantly increased necrotic lesion, TUNEL+ cells, and decreased STAT3 expression in PDX models. *P < 0.05, **P < 0.01, and ***P < 0.001 when compared with the control group. P values are from 2-way ANOVA (C and F), 2-tailed unpaired t test (D and G), or 2-way ANOVA with Tukey’s multiple-comparisons test (I).

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

Sign up for email alerts