Supplementary Figure 4 from EMD 1214063 and EMD 1204831 Constitute a New Class of Potent and Highly Selective c-Met Inhibitors

PDF file - 240K, Dose-dependent inhibition of c-Met auto-phosphorylation in vivo. Panel A: Mice bearing established tumors, derived from s.c. injection of Hs746T gastric cancer cells, received a single dose of 3 mg/kg , 10 mg/kg , 30 mg/kg , and 100 mg/kg EMD 1214063. The pharmacokinetic profile of EMD 1214063 was defined by measuring the compound levels in plasma and tumor tissue. The lower limits of detection for EMD 1214063 were 0.007 �M (4 ng/mL) in the plasma and 0.037 �M (20 ng/mL) in tumor samples. The levels of c-Met auto-phosphorylation (Y1234/Y1235) were assessed by Western blot analysis and used as a pharmacodynamic marker of activity. Each data point represents the mean � SD of the values obtained from four mice per experimental group. A data point was not shown if any of the values within the experimental group was below the detection limit. Panel B: A similar experimental approach to that already described for EMD 1214063 was used to define the pharmacokinetic profile and pharmacodynamic effects of EMD 1204831. In brief, mice bearing established Hs746T subcutaneous tumors received a single dose of 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg EMD 1204831. In the pharmacokinetic studies, the lower limits of detection for EMD 1204831 were 0.014 �M (8 ng/mL) in the plasma and tumor samples. The pharmacodynamic effects were determined by Western blot analyses of c-Met auto-phosphorylation (Y1234/Y1235). Each data point represents the mean � SD of the values obtained from four mice per experimental group. A data point was not shown if any of the values within the experimental group was below the detection limit.