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 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.
|Incubation time||10 min|
|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|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
Developing c-MET pathway inhibitors for cancer therapy: progress and challenges.
Liu et al. Trends Mol Med. 2010 Jan;16(1):37-45. PMID: 20031486.
Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase.
Albrecht BK, et al. J Med Chem. 2008 May 22;51(10):2879-82. PMID: 18426196.
|Related c-Met Products|
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S49076 is a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3 with IC50 values below 20 nmol/L.
Altiratinib(DCC-2701) is a novel c-MET/TIE-2/VEGFR inhibitor; effectively reduce tumor burden in vivo and block c-MET pTyr(1349)-mediated signaling, cell growth and migration as compared with a HGF antagonist in vitro.
MK-2461 is a potent, multi-targeted inhibitor for c-Met(WT/mutants) with IC50 of 0.4-2.5 nM, less potent to Ron, Flt1; 8- to 30-fold greater selectivity of c-Met targets versus FGFR1, FGFR2, FGFR3, PDGFRβ, KDR, Flt3, Flt4, TrkA, and TrkB.
NVP-BVU972 is a selective and potent Met inhibitor with IC50 of 14 nM.
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