c-MET / HGFR - SPR Binding Assay

Theoretical background: c - MET (Mesenchymal epithelial transition factor), also known as hepatocyte growth factor receptor (HGFR) is a receptor tyrosine kinase. The endogenous ligand for c - MET is hepatocyte growth factor/scatter factor (HGF), a disulfide-linked heterodimeric molecule produced predominantly by mesenchymal cells. Ligand-dependent activation of c - MET results in cell proliferation, migration and matrix invasion. These activities facilitate epithelial cell transformation and malignant progression. Thus, abberant activation of the HGF / c - MET pathway leads to a variety of cancers. Amplification of c - MET was also identified as a  mechanism of drug resistance in lung cancer patients initially responsive to the EGFR kinase inhibitors Gefitinib or Erlotinib.

c-MET and inhibitors: SU11274 targets the ATP - binding site of wild type c - MET (IC₅₀ = 20 nM [1]) resulting in an inhibiton of kinase downstream signaling whereas several c - MET mutant forms are resistant to inhibition. AM7, interacting with c - MET in a different binding mode, can bind both the inactive and active form (IC₅₀ = 17 nM [2]) and shows activity against a panel of c - MET mutations found in cancer patients. Crizotinib / PF-2341066 , a multitargeted receptor tyrosine kinase inhibitor, primarily synthesized as ATP - competitive inhibitor for c - MET (IC₅₀ = 11 nM [3]) and ALK is still undergoing clinical trials.