Background:

EMD-1214063 is a selective inhibitor of c-Met with IC50 value of 4 nM. [1]
c-Met is a RTK (receptor tyrosine kinase) which is a single chain precursor protein. The mature form of c-Met conatains alpha and beta subunits, which are disulfide linked to each other. It is normally expressed in stem cells and progenitor cells, which allows these cells to grow invasively in an embryo or regenerate damaged tissues in an adult. The c-Met is a membrane receptor which plays an important role in embryonic development and wound healing. The only known ligand of c-Met receptor is HGF (Hepatocyte growth factor). The c-MET activation by HGF triggers transphosphorylation of the Tyr 1234 and Tyr 1235. The activation of c-Met can activate multiple signal transduction pathways including RAS pathway, PI3K pathway, STAT pathway and Notch pathway. MET pathway is essential for the development of cancer through: angiogenesis, activation of key oncogenic pathways and scatter. The abnormal MET activation means poor prognosis in cancer. [2]
EMD-1214063 inhibited the kinase activity of c-Met with IC50 value of 3 nM in assay using recombinant human c-Met kinase domain. EMD-1214063 can inhibit HGF-induced c-Met phosphorylation with an average IC50 of 6 nM in A549 cells. EMD 1214063 also significantly inhibits the activation of downstream signaling pathways of c-Met including the phosphorylation of Akt, Gab-1and Erk1/2. EMD 1214063 also can inhibit the cell viability with IC40 of less than 1 nM in MKN-45 gastric cancer cells. In cancer xenograft model, EMD-1214063 significantly inhibit the c-Met phosphorylation at 3 mg/kg and inhibit tumor cell proliferation and cyclin D1 expression at 10 mg/kg.[1]
参考文献:
[1]    Bladt F, Faden B, Friese-Hamim M, Knuehl C, Wilm C, Fittschen C, Gradler U, Meyring M, Dorsch D, Jaehrling F et al: EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors. Clin Cancer Res, 19(11):2941-2951.
[2].    Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA: Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 1991, 251(4995):802-804.