title: Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent.
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 IC50. These data are consistent with the hypothesis that S3I-201 is a sub-optimal probe for interrogating STAT3-related cell biology.
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, L5L 1C6, Canada.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Ball
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, L5L 1C6, Canada.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lewis
authors.affiliation: Department of Chemistry, York University, Toronto, Ontario, M3J 1P3, Canada.|Department of Chemistry, Center for Research in Mass Spectrometry, York University, Toronto, Ontario, M3J 1P3, Canada.
authors.forename: Declan
authors.initials: D
authors.lastname: Williams
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Resetca
authors.affiliation: Department of Chemistry, York University, Toronto, Ontario, M3J 1P3, Canada.|Department of Chemistry, Center for Research in Mass Spectrometry, York University, Toronto, Ontario, M3J 1P3, Canada.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Wilson
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L, Canada.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology*; D000636:Aminosalicylic Acids / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D000477:Alkylating Agents; D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; C520337:NSC 74859; D050796:STAT3 Transcription Factor
keywords: NSC 74859; S3I-201; STAT3; covalent modification; oncology