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Molecular Cancer Therapeutics
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Targeting STAT3 with Proteolysis Targeting Chimeras and Next-Generation Antisense Oligonucleotides

Jamie V. Shiah, Jennifer R. Grandis and Daniel E. Johnson
Jamie V. Shiah
Department of Otolaryngology - Head and Neck Surgery, University of California at San Francisco, San Francisco, California.
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Jennifer R. Grandis
Department of Otolaryngology - Head and Neck Surgery, University of California at San Francisco, San Francisco, California.
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Daniel E. Johnson
Department of Otolaryngology - Head and Neck Surgery, University of California at San Francisco, San Francisco, California.
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  • For correspondence: daniel.johnson@ucsf.edu
DOI: 10.1158/1535-7163.MCT-20-0599 Published February 2021
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Abstract

STAT3 has been recognized for its key role in the progression of cancer, where it is frequently upregulated or constitutively hyperactivated, contributing to tumor cell proliferation, survival, and migration, as well as angiogenesis and suppression of antitumor immunity. Given the ubiquity of dysregulated STAT3 activity in cancer, it has long been considered a highly attractive target for the development of anticancer therapies. Efforts to target STAT3, however, have proven to be especially challenging, perhaps owing to the fact that transcription factors lack targetable enzymatic activity and have historically been considered “undruggable.” Small-molecule inhibitors targeting STAT3 have been limited by insufficient selectivity and potency. More recently, therapeutic approaches that selectively target STAT3 protein for degradation have been developed, offering novel strategies that do not rely on inhibition of upstream pathways or direct competitive inhibition of the STAT3 protein. Here, we review these emerging approaches, including the development of STAT3 proteolysis targeting chimera agents, as well as preclinical and clinical studies of chemically stabilized antisense molecules, such as the clinical agent AZD9150. These therapeutic strategies may robustly reduce the cellular activity of oncogenic STAT3 and overcome the historical limitations of less selective small molecules.

Footnotes

  • Mol Cancer Ther 2021;20:219–28

  • Received July 16, 2020.
  • Revision received September 9, 2020.
  • Accepted November 2, 2020.
  • Published first November 17, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (2)
February 2021
Volume 20, Issue 2
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Targeting STAT3 with Proteolysis Targeting Chimeras and Next-Generation Antisense Oligonucleotides
Jamie V. Shiah, Jennifer R. Grandis and Daniel E. Johnson
Mol Cancer Ther February 1 2021 (20) (2) 219-228; DOI: 10.1158/1535-7163.MCT-20-0599

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Targeting STAT3 with Proteolysis Targeting Chimeras and Next-Generation Antisense Oligonucleotides
Jamie V. Shiah, Jennifer R. Grandis and Daniel E. Johnson
Mol Cancer Ther February 1 2021 (20) (2) 219-228; DOI: 10.1158/1535-7163.MCT-20-0599
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  • Article
    • Abstract
    • Introduction
    • Proteolysis Targeting Chimeras
    • PROTACs Targeting STAT3
    • Current Challenges to Development of PROTAC Drugs
    • Antisense Oligonucleotides
    • ASOs Targeting STAT3
    • Small-Molecule Competitive Inhibitors of STAT3
    • Indirect Targeting of STAT3
    • Targeting STAT3 in the Tumor Microenvironment
    • Conclusions
    • Authors' Disclosures
    • Acknowledgments
    • Footnotes
    • References
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Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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