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Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent

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Ball, Daniel P., Lewis, Andrew M., Williams, Declan, Resetca, Diana, Wilson, Derek J., Gunning, Patrick T.·2016·Oncotarget
DOI 10.18632/oncotarget.7838PMC PMC4991483
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Abstract

// Daniel P. Ball 1, * , Andrew M. Lewis 1, * , Declan Williams 2, 3 , Diana Resetca 4 , Derek J. Wilson 2, 3 , Patrick T. Gunning 4 1 Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, L5L 1C6, Canada 2 Department of Chemistry, York University, Toronto, Ontario, M3J 1P3, Canada 3 Department of Chemistry, Center for Research in Mass Spectrometry, York University, Toronto, Ontario, M3J 1P3, Canada 4 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L, Canada * These authors have contributed equally to this work Correspondence to: Patrick T. Gunning, e-mail: patrick.gunning@utoronto.ca Keywords: STAT3, S3I-201, NSC 74859, covalent modification, oncology Received: October 15, 2015 Accepted: January 29, 2016 Published: March 02, 2016 ABSTRACT The Signal Transducer and Activator of Transcription 3 (STAT3) oncogene is a master regulator of many human cancers, and a well-recognized target for therapeutic intervention. A well known STAT3 inhibitor, S3I-201 (NSC 74859), is hypothesized to block STAT3 function in cancer cells by binding the STAT3 SH2 domain and disrupt STAT3 protein complexation events. In this study, liquid chromatography tandem mass spectrometry analysis revealed that STAT3, in the presence of S3I-201, showed a minimum of five specific sites of modification, cysteine’s 108, 259, 367, 542, and 687. Moreover, a prepared fluorescently labeled chemical probe of S3I-201 (DB-6-055) revealed that S3I-201 non-specifically and globally alkylated intracellular proteins at concentrations consistent with S3I-201’s reported IC 50 . These data are consistent with the hypothesis that S3I-201 is a sub-optimal probe for interrogating STAT3-related cell biology.

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  • Some STAT3 inhibitors, such as Stattic and some members of the S3I-201 family, inhibit STAT3 by covalently reacting with residues (largely cysteines) at key locations within STAT3, as well as other off-target proteins.

    “Some, such as Stattic and some members of the S3I-201 family of compounds, inhibit STAT3 by covalently reacting with residues (largely cysteines) at key locations within STAT3, as well as other off-target proteins (Heidelberger et al., 2013; Ball et al., 2016).”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Ball et al., 2016

    The Results show that S3I-201 covalently modifies five STAT3 cysteines, and the Discussion reports cysteine modification by Stattic. The paper also reports widespread alkylation of other cellular proteins by S3I-201. It does not establish that covalent modification is the mechanism by which these compounds inhibit STAT3, or show STAT3 protein modification by other S3I-201-family members. (LLM, conf=0.84)

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Research works printed but not linked: 28

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Cited by

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Authors
Ball, D. P., Lewis, A. M., Williams, D., Resetca, D., Wilson, D. J., & Gunning, P. T.
Affiliations
  • University of Toronto (CA)
  • York University (CA)
Corresponding author
  • Ball, Daniel P.
  • Lewis, Andrew M.
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2016-03-02
Volume
7
Issue
15
Pages
20669-20679
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.7838
PMC
PMC4991483
OpenAlex
W2302340967
Cited by
50
References
0
Citations by year
2026: 1 · 2025: 2 · 2024: 6 · 2023: 2 · 2022: 6 · 2021: 7 · 2020: 11 · 2019: 6 · 2018: 6 · 2017: 2 · 2016: 1
FWCI
2.70
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Natural Sciences and Engineering Research Council of Canada
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Keywords
STAT3, S3I-201, STAT3 inhibitor, alkylating agents, covalent modification, SH2 domain, protein alkylation, cancer therapeutics
MeSH terms
Alkylating Agents, Aminosalicylic Acids, Benzenesulfonates, Breast Neoplasms, Female, Humans, Tumor Cells, Cultured, Apoptosis, Cell Proliferation, STAT3 Transcription Factor

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