AMG-458

Catalog No.S2747

For research use only.

AMG 458 is a potent c-Met inhibitor with Ki of 1.2 nM, ~350-fold selectivity for c-Met than VEGFR2 in cells.

AMG-458 Chemical Structure

CAS No. 913376-83-7

Purity & Quality Control

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Biological Activity

Description AMG 458 is a potent c-Met inhibitor with Ki of 1.2 nM, ~350-fold selectivity for c-Met than VEGFR2 in cells.
Features Completely bioavailable across species and the intrinsic half-life is increased in higher mammals.
Targets
c-Met (H1094R) [1] c-Met (V1092I) [1] c-Met (Human) [1] c-Met (Mouse) [1] c-Met (D1228H) [1] Click to View More Targets
0.5 nM(Ki) 1.1 nM(Ki) 1.2 nM(Ki) 2.0 nM(Ki) 2.2 nM(Ki)
In vitro

AMG 458 also inhibits HGF-mediated c-Met phosphorylation in PC3 and CT26 cells with IC50 of 60 and 120 nM. [1] 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. [2] 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. [3]

In vivo AMG 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. [1] High concentrations of AMG 458 in some organs may produce toxicity via oxidative stress. [2]

Protocol (from reference)

Animal Research:

[1]

  • Animal Models: NIH3T3/TPR-Met and U-87 MG xenograft models are established in female CD-1 nu/nu mice aged 6-8 weeks.
  • Dosages: 10, 30 or 100 mg/kg
  • Administration: Administered via i.v. or p.o.

Solubility (25°C)

In vitro

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
15% Captisol+citrate vehicle
For best results, use promptly after mixing.

30 mg/mL

Chemical Information

Molecular Weight 539.58
Formula

C30H29N5O5

CAS No. 913376-83-7
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC1=C(C(=O)N(N1CC(C)(C)O)C2=CC=CC=C2)C(=O)NC3=NC=C(C=C3)OC4=C5C=CC(=CC5=NC=C4)OC

In vivo Formulation Calculator (Clear solution)

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Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Molarity Calculator

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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