title: 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.affiliation: Departments of Microbiology, University of Virginia, Charlottesville, USA.
authors.forename: Fadila
authors.initials: F
authors.lastname: Guessous
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Charles
authors.initials: C
authors.lastname: diPierro
authors.forename: Lukasz
authors.initials: L
authors.lastname: Marcinkiewicz
authors.forename: Jann
authors.initials: J
authors.lastname: Sarkaria
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: Sean
authors.initials: S
authors.lastname: Buchanan
authors.forename: Roger
authors.initials: R
authors.lastname: Abounader
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001682:Biological Availability; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C547925:6-(6-(1-methyl-1H-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-ylsulfanyl)quinoline; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D014230:Triazoles; D019859:Proto-Oncogene Proteins c-met