American Association for Cancer Research
10780432ccr123247-sup-fig8.pdf (184.52 kB)

Supplementary Figure 8 from EMD 1214063 and EMD 1204831 Constitute a New Class of Potent and Highly Selective c-Met Inhibitors

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journal contribution
posted on 2023-03-31, 17:47 authored by Friedhelm Bladt, Bettina Faden, Manja Friese-Hamim, Christine Knuehl, Claudia Wilm, Claus Fittschen, Ulrich Grädler, Michael Meyring, Dieter Dorsch, Frank Jaehrling, Ulrich Pehl, Frank Stieber, Oliver Schadt, Andree Blaukat

PDF file - 184K, EMD 1214063 and EMD 1204831 display anti-tumor activity in HGF-dependent and HGF-independent xenograft tumor models. Mice bearing subcutaneous tumors derived from the human gastric Hs746T cell line (A and B) or the glioblastoma U87MG cell line (C and D) were administered daily the indicated doses of EMD 1214063 (A and C), EMD 1204831 (B and D), or vehicle for the indicated treatment duration. Each data point represents the mean � SD of the calculated tumor volumes observed in experimental groups including ten mice. Statistical significance was evaluated by one-way ANOVA (Kruskal-Wallis, Dunn's post test). Asterisks indicate statistically significant differences between treated and control experimental groups (P≤0.05).



Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: 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. Clin Cancer Res; 19(11); 2941–51. ©2013 AACR.

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