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

Jinmei Jin1, Yaping Wu2,3, Zeng Zhao4,5

  • 1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

JCI Insight
|December 12, 2022
PubMed

Insights

STAT3 activation drives epithelial cancers. New PROTACs targeting STAT3, like TSM-1, show potent antitumor effects by degrading STAT3, offering a novel therapeutic strategy for head and neck and colorectal cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Aberrant Signal Transducer and Activator of Transcription 3 (STAT3) activation is implicated in epithelial cancers like head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC).
  • Conventional small-molecule inhibitors targeting STAT3 face limitations due to the lack of suitable binding sites, hindering clinical translation.
  • Proteolysis targeting chimeric (PROTAC) technology offers a novel approach to degrade target proteins, overcoming limitations of traditional inhibitors.

Purpose of the Study:

  • To develop and evaluate novel PROTACs as a therapeutic strategy for STAT3-dependent epithelial cancers.
  • To investigate the efficacy and mechanism of action of a lead PROTAC compound, TSM-1, in preclinical models of HNSCC and CRC.

Main Methods:

  • Synthesis of heterobifunctional PROTACs utilizing toosendanin (TSN) as a component, designed to bind STAT3 and an E3 ubiquitin ligase.
  • Evaluation of the optimized PROTAC (TSM-1) in STAT3-dependent HNSCC and CRC models, including patient-derived xenografts (PDX) and organoids (PDO).
  • Mechanistic studies to elucidate the downstream effects of TSM-1 on STAT3 signaling pathways, cell cycle, and apoptosis.

Main Results:

  • Successfully prepared and optimized PROTACs targeting STAT3, with TSM-1 demonstrating superior selectivity and potency.
  • TSM-1 exhibited robust antitumor effects in preclinical models of HNSCC and CRC, including challenging PDX and PDO models.
  • TSM-1 induced cell cycle arrest and apoptosis by reducing the expression of critical STAT3 downstream effectors.

Conclusions:

  • This study demonstrates the successful application of PROTAC technology for targeting STAT3 in epithelial cancers.
  • TSM-1 represents a promising therapeutic candidate for STAT3-dependent HNSCC and CRC, with significant potential for clinical development.
  • The findings establish a novel PROTAC-based strategy for treating STAT3-driven malignancies.
Keywords:
Colorectal cancerDrug therapyHead and neck cancerOncologyTherapeutics

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