AMG 208 is a small molecule inhibitor of c-Met, which inhibits both ligand-dependent and ligand-independent c-Met activation, IC50 = 9.3 nM. The c-MET pathway is dysregulated in most human malignancies, and regulates tumor formation, progression and dissemination, and numerous c-MET pathway inhibitors are currently being evaluated in the clinic. AMG-208 shows the inhibition of HGF-mediated c-Met phosphorylation in PC3 cells with IC50 of 46 nM. 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.
Cell Experiment | |
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Cell lines | PC-3 cells |
Preparation method | Cell-based autophosphorylation assay of c-Met. IC50 measurements of compound activity on HGF-mediated c-Met autophosphorylation were determined in serum-starved PC-3 (human) cells using a quantitative electrochemiluminescent immunoassay. PC3 cells were plated at a density of 20,000 cells/well in 96 well-plates. 24 hours after plating, cells were starved in media containing 0.1% BSA for 18 to 20 hours. Cells were then treated with a 10-point serial dilution of Compound A for one hour at 37℃ followed by stimulation with optimal concentrations of recombinant human HGF for 10 minutes at 37℃. Cells were washed once with PBS and lysed (1% Triton X-100, 50 mM Tris pH 8.0, 100 mM NaCl, 300 µM Na3OV4 and protease inhibitors). Cell lysates were incubated with a biotin-labeled goat–anti-c-Met antibody (BAF358 – for human c-Met, R&D Systems, Minneapolis, MN) for capture followed by a mouse anti-phosphotyrosine antibody 4G10 (Upstate, Charlottesville, VA) and a BV-tagTM labeled anti-mouse IgG (BioVeris Inc., Gaithersburg, MD) as the detection antibody. Levels of c-Met phophorylation were then measured on a BioVeris M-Series instrument. The IC50 values are calculated using Xlfit4-parameter equation. |
Concentrations | IC50=46 nM |
Incubation time | 10 min |
Animal Experiment | |
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Animal models | female Balb/c mice |
Formulation | 2%HPMC, 1%Tween80, in water adjusted to pH 2.2 with HCl |
Dosages | 3, 10, or 30 mg/kg |
Administration | oral gavage |
Molecular Weight | 383.4 |
Formula | C22H17N5O2 |
CAS Number | 1002304-34-8 |
Solubility (25°C) | DMSO 3 mg/mL |
Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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