AMG-208

2 years -80 in solvent

Administered via i.v. and p.o.

AMG-208 is currently in Phase I clinical trials in patients with Advanced Solid Tumors.

AMG-208 is dissolved in DMSO.

AMG-208 shows the potent inhibition of kinase c-Met activity with IC50 of 9 nM in a cell-free assay. Besides, AMG-208 treatment also leads to the inhibition of HGF-mediated c-Met phosphorylation in PC3 cells with IC50 of 46 nM. [1] Incubation of AMG-208 with rat and human liver microsomes in the presence of NADPH qualitatively yields C6-phenylarene oxidation products as the major metabolites. [1] Pre-incubation of AMG-208 with human liver microsomes for 30 minutes shows a potent time-dependent inhibition for CYP3A4 metabolic activity with IC50 of 4.1 uM, which is an eightfold decrease relative to the IC50 (32 uM) without preincubation. [2], AMG-208 is identified to be a c-MET and RON dual selective inhibitor. [3]

In Vitro Kinase Assay, IC50 measurements versus c-Met kinase and its mutants are determined using homogenous time-resolved fluorescence (HTRF) assays., AMG-208 is tested in a 10-point dose-response curve for each enzyme using an ATP concentration of two-thirds Km for each. Most assays consists of enzyme mixed with kinase reaction buffer [20 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 5 mM MnCl2, 100 mM NaCl, 1.5 mM EGTA]. A final concentration of 1 mM DTT, 0.2 mM NaVO4, and 20 ug/mL BSA is added before each assay. For all assays, 5.75 mg/mL streptavidin-allophycocyanin and 0.1125 nM Eu-PT66 are added immediately before the HTRF reaction. Plates are incubated for 30 minutes at room temperature and read on a Discovery instrument Molecules are tested in a 10-point serial dilution for each c-Met construct using an ATP concentration of two thirds Km value that is determined for each enzyme preparation and calculated using the Eadie-Hofstee and Lineweaver-Burke methods.

AMG 208 is a highly selective dual c-Met and RON inhibitor with IC50 of 9 nM for c-Met.