Abstract
The mesenchymal-epithelial transition factor (c-Met) receptor, also known as hepatocyte growth factor receptor (HGFR), controls morphogenesis, a process that is physiologically required for embryonic development and tissue repair. Aberrant c-Met activation is associated with a variety of human malignancies including cancers of the lung, kidney, stomach, liver, and brain. In this study, we investigated the properties of two novel compounds developed to selectively inhibit the c-Met receptor in antitumor therapeutic interventions. The pharmacologic properties, c-Met inhibitory activity, and antitumor effects of EMD 1214063 and EMD 1204831 were investigated in vitro and in vivo, using human cancer cell lines and mouse xenograft models. EMD 1214063 and EMD 1204831 selectively suppressed the c-Met receptor tyrosine kinase activity. Their inhibitory activity was potent [inhibitory 50% concentration (IC50), 3 nmol/L and 9 nmol/L, respectively] and highly selective, when compared with their effect on a panel of 242 human kinases. Both EMD 1214063 and EMD 1204831 inhibited c-Met phosphorylation and downstream signaling in a dose-dependent fashion, but differed in the duration of their inhibitory activity. In murine xenograft models, both compounds induced regression of human tumors, regardless of whether c-Met activation was HGF dependent or independent. Both drugs were well tolerated and induced no substantial weight loss after more than 3 weeks of treatment. Our results indicate selective c-Met inhibition by EMD 1214063 and EMD 1204831 and strongly support clinical testing of these compounds in the context of molecularly targeted anticancer strategies.
Highlights
The mesenchymal–epithelial transition factor (c-Met) has emerged as a promising target in the development of anticancer therapeutics because of its low level of expression in normal tissues and its aberrant activation in many human cancers
The c-Met oncoprotein encodes a prototypic member of the receptor tyrosine kinase superfamily, which binds to the hepatocyte growth factor (HGF), identified as its only high-affinity ligand [1]. c-Met engagement by HGF results in receptor dimerization and autophosphorylation, which in turn activates multiple signaling cascades involved in cell
The biochemical activity of these compounds was measured in a flash-plate assay using recombinant human c-Met kinase domain and a biotinylated peptide substrate
Summary
The mesenchymal–epithelial transition factor (c-Met) has emerged as a promising target in the development of anticancer therapeutics because of its low level of expression in normal tissues and its aberrant activation in many human cancers. C-Met engagement by HGF results in receptor dimerization and autophosphorylation, which in turn activates multiple signaling cascades involved in cell. Targeted deletion of c-Met or HGF severely compromises embryonic development, organ morphogenesis, and cell motility, resulting in early embryonic lethality [3, 4]. C-Met and HGF are detectable only at low levels, with epithelial and mesenchymal cells preferentially expressing c-Met and HGF, respectively. C-Met activation can induce a transdifferentiation program known as epithelial–mesenchymal transition, which results in loss of E-cadherin– mediated tight junctions, thereby conferring on epithelial cells’ mesenchymal characteristics, such as motility and invasiveness [7]
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