EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors.

EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors.

Clin Cancer Res. 2013 Apr 3;

Authors: Bladt F, Faden B, Friese-Hamim M, Knuehl C, Wilm C, Frittschen C, Graedler U, Meyring M, Dorsch D, Jaehrling F, Pehl U, Stieber F, Schadt O, Blaukat A

Abstract
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 anti-tumor therapeutic interventions. EXPERIMENTAL DESIGN: The pharmacologic properties, c-Met inhibitory activity, and anti-tumor 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 nM and 9 nM, respectively) and highly selective, when compared to 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 >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 anti-cancer strategies.

PMID: 23553846 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258