An orally bioavailable c-Met kinase inhibitor potently inhibits brain tumor malignancy and growth

Fadila Guessous, Fadila Zhang, Charles DiPierro, Lukasz Marcinkiewicz, Jann Sarkaria, David Schiff, Sean Buchanan, Roger Abounader

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

The receptor tyrosine kinase, c-Met and its ligand hepatocyte growth factor (HGF) are important regulators of malignancy in human cancer including brain tumors. c-Met is frequently activated in brain tumors and has emerged as a promising target for molecular therapies. Recently, an orally bioavailable small molecule kinase inhibitor of c-Met (SGX523) was developed by SGX Pharmaceuticals. We tested the effects of this inhibitor on c-Met brain tumor cell activation, c-Met-dependent malignancy, and in vivo glioma xenograft growth. SGX523 potently inhibited c-Met activation and c-Met-dependent signaling at nanomolar concentrations in glioma cells, primary gliomas, glioma stem cells and medulloblastoma cells. SGX523 treatment inhibited c-Met-dependent brain tumor cell proliferation and G1/S cell cycle progression. SGX523 also inhibited brain tumor cell migration and invasion. Furthermore, systemic delivery of SGX523 via oral gavage to mice bearing orthotopic human glioblastoma xenografts led to a significant decrease of in vivo tumor growth. These studies show that c-Met activation and c-Met-dependent brain tumor cell and stem cell malignancy can be inhibited by small molecules. The study also shows for the first time that oral delivery of a small molecule kinase inhibitor of c-Met inhibits intracranial tumor growth. These findings suggest that targeting c-Met with small molecule kinase inhibitors is a promising approach for brain tumor therapy. Keywords: c-Met, glioblastoma, hepatocyte growth factor, kinase inhibitor, medulloblastoma, small molecule, scatter factor.

Original languageEnglish (US)
Pages (from-to)28-35
Number of pages8
JournalAnti-Cancer Agents in Medicinal Chemistry
Volume10
Issue number1
DOIs
StatePublished - Jan 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Cancer Research

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