AMG-337 is a potent and selective inhibitor of MET with biochemical IC50 of 1 nM; inhibits of HGF-mediated MET phosphorylation in PC3 cells; shows desirable preclinical pharmacokinetics, significant inhibition of MET phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent mouse efficacy model.Gastric Cancer Phase 2 Clinical(In Vitro):AMG 337 (0-3 μM; 72 h) inhibits proliferation in MET-dependent cancer cell lines.AMG 337 (0-300 nM; 0-24 h; MKN-45, SNU-620, and SNU-5 cells) inhibits signaling through the PI3K and MAPK pathways in MET-amplified gastric cancer cell lines, resulting in an inhibition of MET-dependent cell proliferation and induction of apoptosis.(In Vivo):AMG 337 (0-30 mg/kg; p.o.; daily, for 28 d) inhibits MET signaling in tumor xenografts and inhibits tumor growth in MET-dependent tumor xenograft models.AMG 337 (0-3 mg/kg; p.o.; once, for 3 or 24 h) is associated with increased necrosis in the MET-dependent SNU-620 tumor xenograft model.
AMG 337 (0-30 mg/kg; p.o. ; daily, for 28 d) inhibits MET signaling in tumor xenografts and inhibits tumor growth in MET-dependent tumor xenograft models. AMG 337 (0-3 mg/kg; p.o. ; once, for 3 or 24 h) is associated with increased necrosis in the MET-dependent SNU-620 tumor xenograft model. Animal model: Female CD1 nu/nu mice bearing SNU-620, SNU-5, or U-87 MG xenografts. Dosage: 0, 0.3, and 1 mg/kg (SNU-620 xenograft); 0, 0.3, 1, 3, and 10 mg/kg (SNU-5 xenograft); 0, 3, 10 and 30 mg/kg (U-87 xenograft). Administration: Oral administration; daily, for 28 days. Result: Inhibited tumor growth in MET-dependent tumor xenograft models. Animal model: Female CD1 nu/nu mice bearing SNU-620, SNU-5, or U-87 MG xenografts. Dosage: 0.1, 0.5, 0.75, 1, 2, and 3 mg/kg. Administration: Oral administration; once, for 3 hours. Result: Inhibited Gab-1 phosphorylation in a dose-dependent manner. Animal model: Female CD1 nu/nu mice with SNU-620 xenograft model (6-11 weeks of age; 20-26 g). Dosage: 0, 0.3, 1, and 3 mg/kg. Administration: Oral administration; once, for 3 or 24 hours. Result: Increased immunohistochemical staining with anti-caspase-3 antibody and decreased immunohistochemical staining with anti-BrdU antibody.
In Vitro
AMG 337 (0-3 μM; 72 h) inhibits proliferation in MET-dependent cancer cell lines. AMG 337 (0-300 nM; 0-24 h; MKN-45, SNU-620, and SNU-5 cells) inhibits signaling through the PI3K and MAPK pathways in MET-amplified gastric cancer cell lines, resulting in an inhibition of MET-dependent cell proliferation and induction of apoptosis. Apoptosis Analysis Cell line: MKN-45 and SNU-620 cells. Concentration: 0, 3, 10, 30, 100 and 300 nM. Incubation time: 24 hours. Result: Increased the number of cells undergoing apoptosis. Cell Cycle Analysis Cell line: MKN-45 and SNU-620 cells. Concentration: 0, 3, 10, 30, 100 and 300 nM. Incubation time: 24 hours. Result: Increased in a dose-dependent in cells in the G1 phase and with concurrent reduction of cells in S-phase. Western blot analysis. Cell line: MKN-45, SNU-620, and SNU-5 cells. Concentration: 100 nM. Incubation time: 2 hours. Result: Inhibited MET phosphorylation and phosphorylation of downstream effectors. Western blot analysis. Cell line: MKN-45, SNU-620, and SNU-5 cells. Concentration: 100 nM. Incubation time: 24 hours. Result: Induced PARP and caspase-3 cleavage in SNU-620 and SNU-5 cells.
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