title: Mimics of the dimerization domain of hepatocyte growth factor exhibit anti-Met and anticancer activity.
abstract: The angiotensin IV analog norleual [Nle-Tyr-Leu-ψ-(CH(2)-NH(2))-Leu-His-Pro-Phe] has been shown recently to act as a hepatocyte growth factor (HGF)/Met antagonist capable of blocking the binding of HGF to the Met receptor, inhibiting HGF-dependent activation of Met, and attenuating HGF-dependent cellular activities. In addition, norleual exhibited marked anticancer activity. Homology between norleual and the dimerization domain (hinge region) of HGF led to the hypothesis that norleual acts by interfering with HGF dimerization/multimerization and functions as a dominant-negative hinge region mimic. To test this hypothesis we investigated the ability of norleual to bind to and inhibit the dimerization of HGF. To further evaluate the idea that norleual was acting as a hinge region mimic, we synthesized a hexapeptide representing the HGF hinge sequence and established its capacity to similarly block HGF-dependent activation of Met and HGF-dependent cellular functions. The hinge peptide not only bound with high affinity directly to HGF and blocked its dimerization but it also inhibited HGF-dependent Met activation, suppressed HGF-dependent cellular functions, and exhibited anticancer activity. The major implication of this study is that molecules targeting the dimerization domain of HGF may represent novel and viable anticancer therapeutic agents; the development of such molecules should be feasible using norleual and the hinge peptide as synthetic templates.
authors.affiliation: Department of Veterinary and Comparative, Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, WA 99164-6520, USA.
authors.forename: Leen H
authors.initials: LH
authors.lastname: Kawas
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Yamamoto
authors.forename: John W
authors.initials: JW
authors.lastname: Wright
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Harding
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D017228:Hepatocyte Growth Factor / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D058990:Molecular Targeted Therapy; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D010446:Peptide Fragments; C548782:norleucyl-tyrosyl-leucyl-psi(CH2-NH2)(3-4)-histidyl-prolyl-phenylalanine; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met