Stattic: a small-molecule inhibitor of STAT3 activation and dimerization
Open accessAbstract
Signal transducers and activators of transcription (STATs) are a family of latent cytoplasmic transcription factors that transmit signals from the cell membrane to the nucleus. One family member, STAT3, is constitutively activated by aberrant upstream tyrosine kinase activities in a broad spectrum of cancer cell lines and human tumors. Screening of chemical libraries led to the identification of Stattic, a nonpeptidic small molecule shown to selectively inhibit the function of the STAT3 SH2 domain regardless of the STAT3 activation state in vitro. Stattic selectively inhibits activation, dimerization, and nuclear translocation of STAT3 and increases the apoptotic rate of STAT3-dependent breast cancer cell lines. We propose Stattic as a tool for the inhibition of STAT3 in cell lines or animal tumor models displaying constitutive STAT3 activation.
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Stattic treatment inhibited IL-6-induced STAT3 phosphorylation and nuclear translocation in hepatocytes.
“Stattic treatment inhibited IL-6-induced STAT3 phosphorylation and nuclear translocation in hepatocytes (Schust et al., 2006).”
From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Schust et al., 2006
The Results and Discussion report that Stattic reduced IL-6-induced STAT3 Tyr705 phosphorylation and inhibited cytokine-induced STAT3 nuclear translocation. However, these experiments used HepG2 liver carcinoma cells, not hepatocytes as the citing sentence states. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIncreased apoptosis was observed in STAT3-dependent cancer cell lines upon Stattic treatment.
“Moreover, increased apoptosis was observed in STAT3-dependent cancer cell lines upon Stattic treatment (Schust et al., 2006).”
From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Schust et al., 2006
Stattic blocks activation and dimerization of STAT3.
“Stattic blocks activation and dimerization of STAT3 (Schust et al., 2006) and therefore in our model inhibits the respective conversion of STAT3 to pSTAT3.”
From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Schust et al., 2006
Recent high throughput and in silico screens have the potential to identify novel strategies for targeting STAT3.
“Recent high throughput and in silico screens also have the potential to identify novel strategies for targeting STAT3.101,106”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [101]
STAT3 may be targeted via its SH2 domain by small molecules, peptides, or peptidomimetic compounds.
“STAT3 may be targeted via its SH2 domain by small molecules, peptides, or peptidomimetic compounds.101–104”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [101]
Small molecules, peptides, or peptidomimetic compounds targeting the STAT3 SH2 domain are designed to disrupt STAT3 dimerization, preventing its translocation to the nucleus and transcription.
“Such molecules are designed to disrupt STAT3 dimerization, thus preventing its translocation to the nucleus and transcription.”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [101]
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Cites
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“Stattic treatment inhibited IL-6-induced STAT3 phosphorylation and nuclear translocation in hepatocytes (Schust et al., 2006).”
BackgroundCritical analysis of the potential for targeting STAT3 in human malignancy
Grandis, J., & Peyser (2013) · OncoTargets and Therapy · doi:10.2147/ott.s47903 · Cited by 24 · see citing works
“For example, gene amplification of PDGFR α or EGFR in distinct subsets of glial tumors leads to enhanced expression of those proteins and downstream signaling events, including activation of STAT3.”
Influential
- Authors
- Schust, J., Sperl, B., Hollis, A., Mayer, T. U., & Berg, T.
- Affiliations
- Max Planck Society (DE)
- Corresponding author
- Berg, Thorsten
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2006-11
- Volume
- 13
- Issue
- 11
- Pages
- 1235-1242
- ISSN
- 1074-5521 (ISSN-L)
- OpenAlex
- W2117525838
- Cited by
- 1,105
- References
- 2
- Citations by year
- 2026: 52 · 2025: 58 · 2024: 58 · 2023: 82 · 2022: 76 · 2021: 69 · 2020: 87 · 2019: 87 · 2018: 71 · 2017: 60 · 2016: 62 · 2015: 64 · 2014: 66 · 2013: 54 · 2012: 40
- FWCI
- 9.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion)
- PubMed (publishedVersion)
- KOPS (University of Konstanz) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- Université du Luxembourg
- European Molecular Biology Laboratory
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Stattic, STAT3, small molecule inhibitors, STAT3 activation, STAT3 dimerization, SH2 domain, constitutive STAT3 activation, breast cancer, apoptosis, nuclear translocation, tyrosine kinase signaling, transcription factor inhibition
- MeSH terms
- Cyclic S-Oxides, Humans, Phosphorylation, Apoptosis, src Homology Domains, Dimerization, Cell Line, Tumor, STAT3 Transcription Factor
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