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    AMG-458
    AMG-458

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0600
    CAS #: 913376-83-7Purity ≥98%

    Description: AMG 458 (AMG-458) is a novel c-Met inhibitor with potential anticancer activity. It inhibits c-Met with a Ki of 1 ~ 2.0 nM. AMG-458 demonstrates high in vivo antitumor efficacy in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight.  

    References: J Med Chem. 2008 Jul 10;51(13):3688-91; Chem Res Toxicol. 2008 Nov;21(11):2216-22. 

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    Molecular Weight (MW)539.58
    FormulaC30H29N5O5
    CAS No.913376-83-7
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 21 mg/mL (38.9 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)15% Captisol+citrate vehicle: 30 mg/mL 
    SynonymsAMG-458; AMG 458; AMG458;  

    Chemical Name: 1-(2-hydroxy-2-methylpropyl)-N-(5-((7-methoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

    InChi Key: GLBZSOQDAOLMGC-UHFFFAOYSA-N

    InChi Code: InChI=1S/C30H29N5O5/c1-19-27(29(37)35(20-8-6-5-7-9-20)34(19)18-30(2,3)38)28(36)33-26-13-11-22(17-32-26)40-25-14-15-31-24-16-21(39-4)10-12-23(24)25/h5-17,38H,18H2,1-4H3,(H,32,33,36)

    SMILES Code: O=C(C1=C(C)N(CC(C)(O)C)N(C2=CC=CC=C2)C1=O)NC3=NC=C(OC4=CC=NC5=CC(OC)=CC=C45)C=C3


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    In Vitro

    In vitro activity: AMG 458 also inhibits HGF-mediated c-Met phosphorylation in PC3 and CT26 cells with IC50 of 60 and 120 nM. AMG 458 is observed to bind covalently to liver microsomal proteins from rats and humans in the absence of NADPH. AMG 458 is believed to react with thiol groups in proteins, producing a methoxy quinoline thioether conjugate. A recent study shows that the constitutive phosphorylation of c-Met in H441 is abrogated by AMG 458. The basal and HGF-induced phosphorylation of c-Met in A549 is attenuated by AMG 458. The combination of radiation therapy and AMG 458 treatment is found to synergistically increase apoptosis in the H441 cell line by reduction of p-Akt and p-Erk levels, but not in A549.


    Kinase Assay: AMG 458 is a potent c-Met inhibitor with Ki of 1 nM ~ 2.0 nM. AMG-458 was found to significantly inhibit tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight.


    Cell Assay: AMG 458 also inhibits HGF-mediated c-Met phosphorylation in PC3 and CT26 cells with IC50 of 60 and 120 nM.

    In VivoAMG 458 is metabolically stable in the liver microsomes of mouse, rat, dog, monkey, and human with low intrinsic clearances (Clint:<5, 62, 8, 8, 18 (μL/min)/mg, respectively). When administered orally, AMG 458 achieves remarkably high bioavailability in all species tested. Oral dosing of AMG 458 inhibits HGF-mediated c-Met phosphorylation with an approximate ED90 of 30 mg/kg and an associated plasma exposure of approximately 15 μM at 6 hours. AMG 458 significantly inhibits tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models at 30 and 100 mg/kg q.d. and 30 mg/kg b.i.d.with no adverse effect on body weight. High concentrations of AMG 458 in some organs may produce toxicity via oxidative stress.
    Animal modelFemale CD-1 nu/nu mice aged 6-8) bearing NIH3T3/TPR-Met and U-87 MG xenograft model
    Formulation & DosageFormulated in 20% Captisol with pH adjusted to 3.5 using methanesulfonic acid (i.v. injection); Formulated in 2% HPMC and 1% Tween-80 with pH adjusted to 2.2 using HCl (p.o.); 10, 30, 100 mg/kg; i.v. or p.o.
    ReferencesJ Med Chem. 2008 Jul 10;51(13):3688-91; Chem Res Toxicol. 2008 Nov;21(11):2216-22. 


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    AMG-458

    J. Med. Chem. 2008, 51, 3688–3691

    AMG-458

    Chem. Res. Toxicol. 2008, 21, 2216–2222


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