Research Papers:

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

Daniel P. Ball, Andrew M. Lewis, Declan Williams, Diana Resetca, Derek J. Wilson and Patrick T. Gunning _

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Oncotarget. 2016; 7:20669-20679. https://doi.org/10.18632/oncotarget.7838

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Daniel P. Ball1,*, Andrew M. Lewis1,*, Declan Williams2,3, Diana Resetca4, Derek J. Wilson2,3, Patrick T. Gunning4

1Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, L5L 1C6, Canada

2Department of Chemistry, York University, Toronto, Ontario, M3J 1P3, Canada

3Department of Chemistry, Center for Research in Mass Spectrometry, York University, Toronto, Ontario, M3J 1P3, Canada

4Department 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: [email protected]

Keywords: STAT3, S3I-201, NSC 74859, covalent modification, oncology

Received: October 15, 2015    Accepted: January 29, 2016    Published: March 02, 2016


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 IC50. 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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