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AMG-208

Cat. No. M1647
AMG-208 Structure
Size Price Availability Quantity
Free Sample (0.5-1 mg)  USD 0 In stock
2mg USD 60  USD60 In stock
5mg USD 100  USD100 In stock
10mg USD 170  USD170 In stock
50mg USD 500  USD500 In stock
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Quality Control & Documentation
Biological Activity

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.

Customer Product Validations & Biological Datas
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
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.
Protocol (for reference only)
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
Chemical Information
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
Conversion of different model animals based on BSA (PMID: 27057123)
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.

References

[1] Liu et al. Trends Mol Med. Developing c-MET pathway inhibitors for cancer therapy: progress and challenges.

[2] Albrecht BK, et al. J Med Chem. Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase.

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Keywords: AMG-208 supplier, c-Met, inhibitors, activators


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