Dysregulation of the hepatocyte growth factor (HGF)/Met system often leads to neoplastic changes and cancer, and is one of the most commonly dysregulated systems in cancer. The angiotensin IV analog norleual acts as an HGF/Met antagonist capable of blocking binding of HGF to c-Met. Kawas et al. tested the hypothesis that norleual acts by interfering with HGF dimerization/multimerization and functions as a dominant-negative hinge region mimic. This was tested by synthesizing a hexapeptide representing the hinge-binding region (KDYIRN) of c-Met and demonstrating that this peptide bound directly to HGF with high affinity and also inhibited the dimerization of HGF. The hinge peptide was able to block HGF-dependent Met phosphorylation, cell proliferation, and scattering in the picomolar range. The hinge peptide also demonstrated anticancer activity in vivo by significantly suppressing pulmonary colonization by B16F10 murine melanoma cells in C57BL/6 mice, which are characterized by an overactive HGF/Met system. The major implication of this study is that molecules that target the dimerization domain of HGF could represent novel and viable anticancer therapeutics. These data also support the development of such molecules using norleual and/or the hinge peptide as synthetic templates.
See article at J Pharmacol Exp Ther 2011, 339:509–518
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics