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

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.

• Authors: Fadila Guessous, Ying Zhang, Charles diPierro, Lukasz Marcinkiewicz, Jann Sarkaria, David Schiff, Sean Buchanan, Roger Abounader
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 10 Issue 1 Pg. 28-35 (Jan 2010) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 20015006 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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