Dysregulation of the hepatocyte growth factor (HGF)/Met system often leads to neoplastic changes and to cancer. Kawas et al. reported previously that hexapeptides derived from the HGF hinge binding region mimicked the effects of norleual [Nle-Tyr-Leu-Ψ-(CH2-NH2)3-4-His-Pro-Phe], an angiotensin (Ang) analog (J Pharmacol Exp Ther 2011, 339:509–518). However, norleual is highly unstable, which makes its transition to clinical use problematic. Kawas et al. developed a family of metabolically stabile Ang IV-related analogs referred to as the 6-AH family. The 6-AH family had an improved half-life relative to norleual (t1/2 of 80 versus < 5 min), mimicked the dimerization domain HGF (hinge region), and attenuated the capacity of HGF to activate Met. The 6-AH family member with cysteine at the 2 position was a particularly effective antagonist of HGF-dependent cellular activities. Reduction in pulmonary colonization by B16-F10 melanoma cells demonstrated the efficacy of this stable analog of Ang IV. These studies highlight the ability of Ang IV-like molecules to bind to HGF, block HGF dimerization, and inhibit the HGF/Met system. Moreover, these data encourage the development of Ang IV-related pharmaceuticals as therapeutic agents in disorders for which inhibition of the HGF/Met system would be clinically advantageous.
See article at J Pharmacol Exp Ther 2012, 340:539–548.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics