title: EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: EMD Serono and Merck Serono Research and Development, Merck KGaA, Darmstadt, Germany. Friedhelm.Bladt@merckgroup.com
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Bladt
authors.forename: Bettina
authors.initials: B
authors.lastname: Faden
authors.forename: Manja
authors.initials: M
authors.lastname: Friese-Hamim
authors.forename: Christine
authors.initials: C
authors.lastname: Knuehl
authors.forename: Claudia
authors.initials: C
authors.lastname: Wilm
authors.forename: Claus
authors.initials: C
authors.lastname: Fittschen
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grädler
authors.forename: Michael
authors.initials: M
authors.lastname: Meyring
authors.forename: Dieter
authors.initials: D
authors.lastname: Dorsch
authors.forename: Frank
authors.initials: F
authors.lastname: Jaehrling
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pehl
authors.forename: Frank
authors.initials: F
authors.lastname: Stieber
authors.forename: Oliver
authors.initials: O
authors.lastname: Schadt
authors.forename: Andree
authors.initials: A
authors.lastname: Blaukat
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C585468:4-(2-(2-(3-(3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyridazin-1-ylmethyl)phenyl)pyrimidin-5-yloxy)ethyl)morpholine; D000970:Antineoplastic Agents; C582858:EMD1214063; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D019859:Proto-Oncogene Proteins c-met