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Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma.
ACS Med Chem Lett. 2013 Nov 14; 4(11):1102-7.AM

Abstract

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.

Authors+Show Affiliations

Department of Chemical and Physical Sciences, University of Toronto at Mississauga , Mississauga, ON L5L 1C6, Canada.Hotchkiss Brain Institute and Department of Cell Biology and Anatomy, University of Calgary , Calgary, AB T2N 1N4, Canada.Department of Chemical and Physical Sciences, University of Toronto at Mississauga , Mississauga, ON L5L 1C6, Canada.Department of Chemistry, University of Toronto at Scarborough , Toronto, ON M1C 1A4, Canada.Department of Chemical and Physical Sciences, University of Toronto at Mississauga , Mississauga, ON L5L 1C6, Canada.Department of Chemistry, University of Toronto at Scarborough , Toronto, ON M1C 1A4, Canada.Department of Chemical and Physical Sciences, University of Toronto at Mississauga , Mississauga, ON L5L 1C6, Canada.Cell Biology Program and James Burrel Laboratories at the Hospital for Sick Children , Toronto, ON M5G 1X8, Canada.Department of Chemical and Physical Sciences, University of Toronto at Mississauga , Mississauga, ON L5L 1C6, Canada.Department of Chemistry, University of Toronto at Scarborough , Toronto, ON M1C 1A4, Canada.Cell Biology Program and James Burrel Laboratories at the Hospital for Sick Children , Toronto, ON M5G 1X8, Canada.Drug Discovery Program, Ontario Institute for Cancer Research , Toronto, ON M5G 0A3, Canada.Drug Discovery Program, Ontario Institute for Cancer Research , Toronto, ON M5G 0A3, Canada.Drug Discovery Program, Ontario Institute for Cancer Research , Toronto, ON M5G 0A3, Canada.Hotchkiss Brain Institute and Department of Cell Biology and Anatomy, University of Calgary , Calgary, AB T2N 1N4, Canada.Department of Chemical and Physical Sciences, University of Toronto at Mississauga , Mississauga, ON L5L 1C6, Canada.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24900612

Citation

Haftchenary, Sina, et al. "Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: a Promising Route for Treating Glioblastoma." ACS Medicinal Chemistry Letters, vol. 4, no. 11, 2013, pp. 1102-7.
Haftchenary S, Luchman HA, Jouk AO, et al. Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma. ACS Med Chem Lett. 2013;4(11):1102-7.
Haftchenary, S., Luchman, H. A., Jouk, A. O., Veloso, A. J., Page, B. D., 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. (2013). Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma. ACS Medicinal Chemistry Letters, 4(11), 1102-7. https://doi.org/10.1021/ml4003138
Haftchenary S, et al. Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: a Promising Route for Treating Glioblastoma. ACS Med Chem Lett. 2013 Nov 14;4(11):1102-7. PubMed PMID: 24900612.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma. AU - Haftchenary,Sina, AU - Luchman,H Artee, AU - Jouk,Andriana O, AU - Veloso,Anthony J, AU - Page,Brent D G, AU - Cheng,Xin Ran, AU - Dawson,Sean S, AU - Grinshtein,Natalie, AU - Shahani,Vijay M, AU - Kerman,Kagan, AU - Kaplan,David R, AU - Griffin,Carly, AU - Aman,Ahmed M, AU - Al-Awar,Rima, AU - Weiss,Samuel, AU - Gunning,Patrick T, Y1 - 2013/09/08/ PY - 2013/08/13/received PY - 2013/09/08/accepted PY - 2014/6/6/entrez PY - 2014/6/6/pubmed PY - 2014/6/6/medline KW - STAT3 KW - anticancer drug KW - brain cancer stem cells KW - glioblastoma KW - protein-protein interactions KW - small-molecule inhibitor SP - 1102 EP - 7 JF - ACS medicinal chemistry letters JO - ACS Med Chem Lett VL - 4 IS - 11 N2 - 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. SN - 1948-5875 UR - https://www.unboundmedicine.com/medline/citation/24900612/Potent_Targeting_of_the_STAT3_Protein_in_Brain_Cancer_Stem_Cells:_A_Promising_Route_for_Treating_Glioblastoma_ L2 - https://dx.doi.org/10.1021/ml4003138 DB - PRIME DP - Unbound Medicine ER -
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