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

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 ST...

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Autores principales: Ball, Daniel P., Lewis, Andrew M., Williams, Declan, Resetca, Diana, Wilson, Derek J., Gunning, Patrick T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Research Paper
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991483/
https://www.ncbi.nlm.nih.gov/pubmed/26942696
http://dx.doi.org/10.18632/oncotarget.7838
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author Ball, Daniel P.
Lewis, Andrew M.
Williams, Declan
Resetca, Diana
Wilson, Derek J.
Gunning, Patrick T.
author_facet Ball, Daniel P.
Lewis, Andrew M.
Williams, Declan
Resetca, Diana
Wilson, Derek J.
Gunning, Patrick T.
author_sort Ball, Daniel P.
collection PubMed
description 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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spelling pubmed-49914832016-09-01 Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent Ball, Daniel P. Lewis, Andrew M. Williams, Declan Resetca, Diana Wilson, Derek J. Gunning, Patrick T. Oncotarget Research Paper 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. Impact Journals LLC 2016-03-02 /pmc/articles/PMC4991483/ /pubmed/26942696 http://dx.doi.org/10.18632/oncotarget.7838 Text en Copyright: © 2016 Ball et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Ball, Daniel P.
Lewis, Andrew M.
Williams, Declan
Resetca, Diana
Wilson, Derek J.
Gunning, Patrick T.
Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent
title Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent
title_full Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent
title_fullStr Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent
title_full_unstemmed Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent
title_short Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent
title_sort signal transducer and activator of transcription 3 (stat3) inhibitor, s3i-201, acts as a potent and non-selective alkylating agent
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991483/
https://www.ncbi.nlm.nih.gov/pubmed/26942696
http://dx.doi.org/10.18632/oncotarget.7838
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