Home Protein Tyrosine Kinase c-Met inhibitor AMG-458

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AMG-458 c-Met inhibitor

Cat.No.S2747

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 c-Met inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 539.58

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Chemical Information, Storage & Stability

Molecular Weight 539.58 Formula

C30H29N5O5

 Storage (From the date of receipt)
CAS No. 913376-83-7 Download SDF Storage of Stock Solutions

Synonyms N/A 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

Solubility

In vitro
Batch:

DMSO : 26 mg/mL ( (48.18 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble

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Mass Concentration Volume Molecular Weight

In vivo
Batch:

In vivo Formulation Calculator (Clear solution)

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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.
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Mechanism of Action

Features
Completely bioavailable across species and the intrinsic half-life is increased in higher mammals.
Targets/IC50/Ki
c-Met (H1094R) [1]
0.5 nM(Ki)
c-Met (V1092I) [1]
1.1 nM(Ki)
c-Met (Human) [1]
1.2 nM(Ki)
c-Met (Mouse) [1]
2.0 nM(Ki)
c-Met (D1228H) [1]
2.2 nM(Ki)
c-Met (M1250T) [1]
4.1 nM(Ki)
c-Met (Y1230H) [1]
4.5 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]
References

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