JCI Insight (Nov 2022)

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

  • 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 volume & issue
Vol. 7, no. 22

Abstract

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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.

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