Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent
Why this work is in the frame
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Bibliographic record
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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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it