Research ArticleCancer

Blockade of Glioma Proliferation Through Allosteric Inhibition of JAK2

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Sci. Signal.  09 Jul 2013:
Vol. 6, Issue 283, pp. ra55
DOI: 10.1126/scisignal.2003900

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Combating Glioblastoma Allosterically

In many cancers, the gene that encodes the epidermal growth factor receptor (EGFR) is overexpressed or mutated; in addition, the most aggressive glioblastomas also have mutation or deletion of the gene encoding PTEN (phosphatase and tensin homolog). He et al. discovered an allosteric inhibitor of JAK2 (Janus kinase 2), called G5-7, that selectively blocked JAK2-mediated phosphorylation and activation of EGFR and STAT3 (signal transducer and activator of transcription 3), inducers of cell proliferation and metabolism. G5-7 inhibited the in vitro proliferation of PTEN-deficient glioblastoma cell lines and reduced the in vivo abundance of angiogenic and proliferation markers in intracranial xenografts in mice. Moreover, G5-7 improved the survival of tumor-bearing mice and was more potent than currently available competitive inhibitors of EGFR or JAK2 at reducing glioblastoma cell proliferation in vitro, suggesting that this allosteric JAK2 inhibitor may be an effective treatment for PTEN-deficient glioblastoma.