Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma
Open accessAbstract
The STAT3 gene is abnormally active in glioblastoma (GBM) and is a critically important mediator of tumor growth and therapeutic resistance in GBM. Thus, for poorly treated brain cancers such as gliomas, astrocytomas, and glioblastomas, which harbor constitutively activated STAT3, a STAT3-targeting therapeutic will be of significant importance. Herein, we report a most potent, small molecule, nonphosphorylated STAT3 inhibitor, 31 (SH-4-54) that strongly binds to STAT3 protein (K D = 300 nM). Inhibitor 31 potently kills glioblastoma brain cancer stem cells (BTSCs) and effectively suppresses STAT3 phosphorylation and its downstream transcriptional targets at low nM concentrations. Moreover, in vivo, 31 exhibited blood-brain barrier permeability, potently controlled glioma tumor growth, and inhibited pSTAT3 in vivo. This work, for the first time, demonstrates the power of STAT3 inhibitors for the treatment of BTSCs and validates the therapeutic efficacy of a STAT3 inhibitor for GBM clinical application.
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SH-4-54 is a commercially available STAT3 phosphorylation site inhibitor reported to cross the blood-brain barrier.
“To test this possibility, we resorted to a commercially available STAT3 phosphorylation site inhibitor SH-4-54 that was reported to cross the blood-brain barrier (Haftchenary et al., 2013).”
From Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease (2018) · cites this paper as Haftchenary et al., 2013
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Self-citation
- Authors
- Haftchenary, S., Luchman, H. A., Jouk, A. O., Veloso, A. J., Page, B. D. G., Cheng, X. R., Dawson, S. S., Grinshtein, N., Shahani, V. M., Kerman, K., Kaplan, D. R., Griffin, C., Aman, A. M., Al-awar, R., Weiss, S., & Gunning, P. T.
- Affiliations
- University of Toronto (CA)
- University of Calgary (CA)
- Hospital for Sick Children (CA)
- Department of Chemistry, University of Toronto at Scarborough, Toronto, ON M1C 1A4, Canada
- Ontario Institute for Cancer Research (CA)
- Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada
- Corresponding author
- Weiss, Samuel
- Gunning, Patrick T.
- ORCID
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-09-16
- Volume
- 4
- Issue
- 11
- Pages
- 1102-1107
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC4027491
- OpenAlex
- W2033091977
- Cited by
- 126
- References
- 28
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 9 · 2023: 4 · 2022: 6 · 2021: 9 · 2020: 13 · 2019: 19 · 2018: 12 · 2017: 9 · 2016: 13 · 2015: 18 · 2014: 3
- FWCI
- 5.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Medicinal Chemistry Letters (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- STAT3, glioblastoma, STAT3 inhibitor, small molecule inhibitors, STAT3 phosphorylation, blood-brain barrier permeability, treatment resistance
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