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Author Notes:

Corresponding author: kye@emory.edu

K.H. and Q.Q. contributed equally to this work.

K.H., Q.Q., and K.Y. designed the study, interpreted the data, and wrote the paper.

K.H., Q.Q., C.-B.C., G.X., and X. Liu performed cell proliferation, cell cycle analysis, Western blotting, and kinase assay.

C.T.-B. and D.J.B. performed in vivo neurosphere experiments.

L.W. and H.M. performed MRI for brain tumors.

X. Lu and F.E.M. performed the synthesis and structure analysis of G5-7.

Q.-W.F. and W.A.W. provided the EGFR stable transfected LN229 and SF763 cell lines.

S.-Y.S. performed apoptosis experiments.

H.L. contributed to the experimental design.

We are thankful to P. Mischel at the University of California, Los Angeles, for the U87MG stable transfected cell lines; H.-W. Lo at Duke University for the human astrocyte cells; and S. Frank at the University of Alabama at Birmingham for the JAK2 plasmids.

Competing interests: Emory University supports sharing of materials through a Materials Transfer Agreement. Emory University has filed a patent application for the use of this compound and its related derivatives as anticancer drugs.


Research Funding:

This work was supported by grants from the NIH (RO1CA127119) to K.Y., the Samuel Waxman Cancer Research Foundation to Q.-W.F. and W.A.W., and unrestricted funding from the Department of Chemistry, Emory University to X.L. and F.E.M.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology

Blockade of Glioma Proliferation Through Allosteric Inhibition of JAK2

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Journal Title:

Science Signaling


Volume 6, Number 283


, Pages ra55-ra55

Type of Work:

Article | Post-print: After Peer Review


The gene that encodes the epidermal growth factor receptor (EGFR) is frequently overexpressed or mutated in human cancers, including glioblastoma. However, the efficacy of EGFR-targeted small-molecule inhibitors or monoclonal antibodies in glioblastomas that also have mutation or deletion of the gene encoding phosphatase and tensin homolog (PTEN) has been modest. We found that EGFR signaling was blocked by a small molecule (G5-7) that selectively inhibited Janus kinase 2 (JAK2)-mediated phospho-rylation and activation of EGFR and STAT3 (signal transducer and activator of transcription 3) by binding to JAK2, thereby decreasing the activity of downstream signaling by mTOR (mammalian target of rapamycin) and inducing cell cycle arrest. G5-7 inhibited the proliferation of PTEN-deficient glioblastoma cell lines harboring a constitutively active variant of EGFR (U87MG/EGFRvIII) and human glioblastoma explant neu-rosphere cultures, but the drug only weakly inhibited the proliferation of either glioblastoma cell lines that were wild type for EGFR and stably transfected with PTEN (U87MG/PTEN) or normal neural progenitor cells and astrocytes. Additionally, G5-7 reduced vascular endothelial growth factor (VEGF) secretion and endothelial cell migration and induced apoptosis in glioblastoma xenografts, thereby suppressing glioblastoma growth in vivo. Furthermore, G5-7 was more potent than EGFR or JAK2 inhibitors that interfere with either ligand or adenosine 5′-triphosphate (ATP) binding at impeding glioblastoma cell proliferation, demonstrating that this allosteric JAK2 inhibitor may be an effective clinical strategy.

Copyright information:

© 2008 American Association for the Advancement of Science. All Rights Reserved.

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