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ACS Med Chem Lett. 2013 Sep 8;4(11):1102-7. doi: 10.1021/ml4003138. eCollection 2013 Nov 14.

Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma.

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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 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.


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.


STAT3; anticancer drug; brain cancer stem cells; glioblastoma; protein-protein interactions; small-molecule inhibitor

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