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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.
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Source | Oncotarget (2015). Figure 3. AMG-208 |
| Method | oral | |
| Cell Lines | ||
| Concentrations | 25, 50, 100, 150, 200, 300, and 400 mg | |
| Incubation Time | 72 h | |
| Results | PlGF demonstrated a pharmacodynamic response to AMG 208; mean PlGF levels increased the most with the 400-mg dose at all time points |
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Source | Oncotarget (2015). Figure 2. AMG-208 |
| Method | oral | |
| Cell Lines | ||
| Concentrations | 25, 50, 100, 150, 200, 300, and 400 mg | |
| Incubation Time | 72 h | |
| Results | AMG 208 mean plasma half-life estimates ranged from 21.4 to 68.7 hours and were consistent with a 1.81- to 3.43-fold accumulation observed after 28 days of repeated dosing. |
| Cell Experiment | |
|---|---|
| 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 | |
|---|---|
| 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 |
| Related c-Met Products |
|---|
| Zurletrectinib
Zurletrectinib (ICP-723) is a potent tyrosine kinase inhibitor. Zurletrectinib serves as an antineoplastic agent. Zurletrectinib can used for research of TRK-mediated related diseases. |
| ABN401
ABN401 is a highly potent and selective ATP-competitive c-MET inhibitor with an IC50 value of 10 nM. |
| (Z)-Semaxanib
(Z)-Semaxanib is a potent tyrosine kinase inhibitor. |
| MET kinase-IN-2
MET kinase-IN-2 is a potent, selective, orally bioavailable MET kinase inhibitor with an IC50 of 7.4 nM. |
| BMS-817378
BMS-817378 is a potent and selective inhibitor of MET with IC50 of 1.7 nM. |
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