AMG 458

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].

in vivo

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.

target

c-Met (H1094R)

IC 50

VEGDR2: 4100 nM (Ki)

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.