AMG-458

Catalog No.S2747

AMG-458 Chemical Structure

Molecular Weight(MW): 539.58

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

Size Price Stock Quantity  
In DMSO USD 580 In stock
USD 270 In stock
USD 370 In stock
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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]
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

Animal Research:

[1]

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  • Animal Models: NIH3T3/TPR-Met and U-87 MG xenograft models are established in female CD-1 nu/nu mice aged 6-8 weeks.
  • Formulation: i.v. dose: 1 mg/kg (20% Captisol with pH adjusted to 3.5 using methanesulfonic acid). p.o. dose: 10 mg/kg (2% HPMC and 1% Tween-80 with pH adjusted to 2.2 using HCl). Both are solution formulations with the same drug concentration of 1 mg/mL.
  • Dosages: 10, 30 or 100 mg/kg
  • Administration: Administered via i.v. or p.o.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 21 mg/mL (38.91 mM)
Water Insoluble
Ethanol Insoluble
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

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 539.58
Formula

C30H29N5O5

CAS No. 913376-83-7
Storage powder
in solvent
Synonyms N/A

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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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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID