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

Clin Cancer Res. 2013 Jun 1;19(11):2941-51. doi: 10.1158/1078-0432.CCR-12-3247. Epub 2013 Apr 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • 4-(2-(2-(3-(3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyridazin-1-ylmethyl)phenyl)pyrimidin-5-yloxy)ethyl)morpholine
  • Antineoplastic Agents
  • EMD1214063
  • Morpholines
  • Protein Kinase Inhibitors
  • Pyridazines
  • Pyrimidines
  • Proto-Oncogene Proteins c-met