期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 4, 期 11, 页码 1102-1107出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml4003138
关键词
STAT3; brain cancer stem cells; glioblastoma; small-molecule inhibitor; protein-protein interactions; anticancer drug
资金
- Boehringer Ingelheim Canada
- Stem Cell Network
- NSERC Discovery Grant
- NSERC Graduate Scholarship
- Ontario Graduate Scholarship
- Alberta Innovates [201201230] Funding Source: researchfish
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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