AMG 458

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.