論文 - 詳細
| RRC ID | 44369 |
|---|---|
| 著者 | Bladt F, Faden B, Friese-Hamim M, Knuehl C, Wilm C, Fittschen C, Grädler U, Meyring M, Dorsch D, Jaehrling F, Pehl U, Stieber F, Schadt O, Blaukat A. |
| タイトル | EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors. |
| ジャーナル | Clin Cancer Res |
| 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 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. |
| 巻・号 | 19(11) |
| ページ | 2941-51 |
| 公開日 | 2013-6-1 |
| DOI | 10.1158/1078-0432.CCR-12-3247 |
| PII | 1078-0432.CCR-12-3247 |
| PMID | 23553846 |
| MeSH | Animals Antineoplastic Agents / administration & dosage Antineoplastic Agents / pharmacology* Cell Line, Tumor Cell Movement / drug effects Cell Proliferation / drug effects Dose-Response Relationship, Drug Humans Mice Morpholines / pharmacology* Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins c-met / antagonists & inhibitors* Pyridazines / administration & dosage Pyridazines / pharmacology* Pyrimidines / administration & dosage Pyrimidines / pharmacology* Signal Transduction / drug effects Xenograft Model Antitumor Assays |
| IF | 10.107 |
| 引用数 | 51 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | LoVo(RCB1639) HCT116(RCB2979) |