The Angiotensin IV analogs D‐Nle‐X‐Ile‐NH‐(CH2)5‐COOH (6AH family) can act as Hepatocyte Growth Factor/c‐Met modifiers

Abstract

The 6AH family [D-Nle-X-Ile-NH-(CH2)5-COOH; where X= various amino acids] of Angiotensin IV analogs, exhibit structural similarities to Hepatocyte Growth Factor (HGF) hinge (linker) region, and act as a hinge region mimics. Members of the 6AH family bind directly to HGF and block its dimerization, a process required for both ligand (HGF) and its receptor (c-Met) activation. This interference translates into inhibition of HGF-dependent signaling, proliferation, and scattering in multiple cell types at concentration reaching down into the low picomolar range. Additionally, a member of the family with Cysteine at position 2 is a particularly effective antagonist of HGF-dependent cellular activities. Not surprisingly it significantly suppresses pulmonary colonization by B16-F10 murine melanoma cells, which are characterized by an overactive HGF/c-Met system. In contrast to modifications of the number two X position alterations of the number one D-Norleucine can convert these compounds into HGF mimetics. Together these data indicate that AngIV analogs can exert at least some of their biological activity by modifying the activity of the HGF/c-Met system and have the potential to be utilized as therapeutic agents in disorders that are dependent on or sensitive to alterations of the HGF/c-Met system. The project was funded by Autzen foundation.