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

Anticancer Agents Med Chem. 2010 Jan;10(1):28-35. doi: 10.2174/1871520611009010028.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Biological Availability
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Flow Cytometry
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • Humans
  • Mice
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Pyridazines / pharmacokinetics
  • Pyridazines / pharmacology
  • Pyridazines / therapeutic use*
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology
  • Triazoles / therapeutic use*


  • 6-(6-(1-methyl-1H-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-ylsulfanyl)quinoline
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyridazines
  • Triazoles
  • Proto-Oncogene Proteins c-met