Investigation of the protein alkylation sites of the STAT3:STAT3 inhibitor Stattic by mass spectrometry
Abstract
STAT3 (Signal Transducer and Activator of Transcription factor 3) is constitutively active in a wide range of human tumours. Stattic is one of the first non-peptidic small molecules reported to inhibit formation of the STAT3:STAT3 protein dimer complex. A mass spectrometry method has been developed to investigate the binding of Stattic to the un-phosphorylated STAT3βtc (U-STAT3) protein. Alkylation of four cysteine residues has been observed with possible reaction at a fifth which could account for the mechanism of action.
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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 Heidelberger et al., 2013
Cites
Darnell, J. E., Kerr, L. M., & Stark, G. R. (1994) · Science · doi:10.1126/science.8197455 · Cited by 6,080 · see citing works
Bowman, T., Garcia, R., Turkson, J., & Jove, R. (2000) · Oncogene · doi:10.1038/sj.onc.1203527 · Cited by 1,743 · see citing works
The role of STATs in transcriptional control and their impact on cellular function
Bromberg, J., & Darnell, J. E. (2000) · Oncogene · doi:10.1038/sj.onc.1203476 · Cited by 1,201 · see citing works
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“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 locationswithinSTAT3, as well as other off-target proteins (Heidelberger et al., 2013; Ball et al., 2016).”
Background
- Authors
- Heidelberger, S., Zinzalla, G., Antonow, D., Essex, S., Piku Basu, B., Palmer, J., Husby, J., Jackson, P. J. M., Rahman, K. M., Wilderspin, A. F., Zloh, M., & Thurston, D. E.
- Affiliations
- UCL School of Pharmacy (GB)
- Karolinska Institutet (SE)
- King's College London (GB)
- Corresponding author
- Thurston, David E.
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 23
- Issue
- 16
- Pages
- 4719-4722
- ISSN
- 0960-894X (ISSN-L)
- OpenAlex
- W2083532042
- Cited by
- 52
- References
- 3
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2022: 2 · 2021: 6 · 2020: 11 · 2019: 7 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 3 · 2014: 2
- FWCI
- 2.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- University of Hertfordshire Research Archive (University of Hertfordshire) (submittedVersion)
- Funders
- Cancer Research UK (C180/A9327)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- STAT3, Stattic, protein alkylation, cysteine residues, small molecule inhibitors, binding mechanism
- MeSH terms
- Alkylating Agents, Amino Acid Sequence, Binding Sites, Cyclic S-Oxides, Humans, Models, Molecular, Proteins, Mass Spectrometry, Molecular Structure, Dimerization, STAT3 Transcription Factor
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