化合物信息

Description

Solid tumours

Description

AMG-208 is a highly selective c-Met inhibitor with IC50 of 9.3 nM.

Targets

IC₅₀

In Vitro

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 μM, which is an eightfold decrease relative to the IC50 (32 μM) without preincubation. ^[2] AMG-208 is identified to be a c-MET and RON dual selective inhibitor. ^[3]

In Vivo

In male Sprague?Dawley rats, AMG-208 (0.5 mg/kg i.v.) shows a high bioavailability with Cl of 0.37 L/h/kg, V_ss of 0.38 L/kg and T_1/2 of 1 hour, while AMG-208 (2 mg/kg i.v.) shows a bioavailability with AUC_0→∞ of 2517 ng·h/mL and F of 43%, respectively. ^[1]

Clinical Trials

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

Features

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 K_m 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 μg/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.

Animal Models

Male Sprague-Dawley rats

Formulation

AMG-208 is dissolved in DMSO.

Doses

≤2 mg/kg

Administration

Administered via i.v. and p.o.