913376-83-7 Usage
Uses
AMG-458 is a potent inhibitor of c-Met with an IC50 of 60 nM.
Biological Activity
amg-458 is a potent and selective inhibitor of human and mouse c-met with ic50 value of 1.2 nm and 2.0 nm respectively.c-met, also known as hepatocyte growth factor receptor, is a receptor tyrosine kinase that can be activated by hepatocyte growth factor/scatter factor (hgf/sf). it is a membrane protein which plays an essential role in embryonic development and wound healing.recent study investigated the effect of amg-456 treatment on cell radiosensitizing response. the results showed that amg-458 treatment enhanced radiosensitivity in h441 with higher levels of c-met but not in a549 with lower expression of c-met [1].this component was also used in an animal model to study the role of c-met in the development of tumor. for instance, orally administration of amg-456 resulted in significant inhibition of tumor growth in /tpr-met and u-87 mg xenograft models without any adverse effect on body weight [2].
Enzyme inhibitor
This potent c-Met protein kinase inhibitor (FW = 539.58 g/mol; CAS 913376-83-7; Solubility: 21 mg/mL DMSO; ~1 mg/mL H2O), also named 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin- 2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide, targets the MET proto-oncogene product c-Met, which is the hepatocyte growth factor receptor possessing tyrosine-kinase activity. The primary single-chain precursor protein is posttranslationally cleaved to produce the a and b subunits that are disulfide linked to form the mature receptor. Various mutations in the MET gene are associated with papillary renal carcinoma. AMG-458 preferentially inhibits c-Met (Ki = 1.2 nM), showing ~350-fold greater potency than VEGFR2 in cells. AMG-458 significantly inhibited tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight. AMG 458 binds covalently to liver microsomal proteins from rats and humans, even in the absence of NADPH. When [14C]AMG-458 is incubated with liver microsomes in the presence of glutathione or N-acetyl cysteine, quinolone-type thioether adducts can be detected by radiochromatographyand LC/MS/MS analysis. AMG-458 was more effective in cells that expressed higher levels of c-Met/p-Met, suggesting that higher levels of c- Met and p-Met in non-small cell lung cancer (NSCLC) tissue may classify a subset of tumors that are more sensitive to molecular therapies against this receptor.
references
1. li b, torossian a, sun y, du r, dicker ap, lu b. higher levels of c-met expression and phosphorylation identify cell lines with increased sensitivity to amg-458, a novel selective c-met inhibitor with radiosensitizing effects. int j radiat oncol biol phys 2012,84:e525-531.2. liu l, siegmund a, xi n, kaplan-lefko p, rex k, chen a, et al. discovery of a potent, selective, and orally bioavailable c-met inhibitor: 1-(2-hydroxy-2-methylpropyl)-n-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-meth yl-3-oxo-2-phenyl-2,3-dihydro-1h-pyrazole-4-carboxamide (amg 458). j med chem 2008,51:3688-3691.
Check Digit Verification of cas no
The CAS Registry Mumber 913376-83-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 9,1,3,3,7 and 6 respectively; the second part has 2 digits, 8 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 913376-83:
(8*9)+(7*1)+(6*3)+(5*3)+(4*7)+(3*6)+(2*8)+(1*3)=177
177 % 10 = 7
So 913376-83-7 is a valid CAS Registry Number.
913376-83-7Relevant academic research and scientific papers
Discovery of a potent, selective, and orally bioavailable c-met inhibitor: 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl) -5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458)
Liu, Longbin,Siegmund, Aaron,Xi, Ning,Kaplan-Lefko, Paula,Rex, Karen,Chen, April,Lin, Jasmine,Moriguchi, Jodi,Berry, Loren,Huang, Liyue,Teffera, Yohannes,Yang, Yajing,Zhang, Yihong,Bellon, Steven F.,Lee, Matthew,Shimanovich, Roman,Bak, Annette,Dominguez, Celia,Norman, Mark H.,Harmange, Jean-Christophe,Dussault, Isabelle,Kim, Tae-Seong
supporting information; experimental part, p. 3688 - 3691 (2009/04/11)
Deregulation of the receptor tyrosine kinase c-Met has been implicated in human cancers. Pyrazolones with N-1 bearing a pendent hydroxyalkyl side chain showed selective inhibition of c-Met over VEGFR2. However, studies revealed the generation of active, n
SUBSTITUTED AMIDE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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Page/Page column 126, (2008/06/13)
Selected compounds are effective for prophylaxis and treatment of diseases, such as HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
