AMG-208

• 产品号: S1316
• CAS号: 1002304-34-8
• 分子式: C22H17N5O2
• 分子量: 383.40268
• 保 存: -20°C

产品别名

• 标题: AMG-208
• IUPAC标准名: 7-methoxy-4-({6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl}methoxy)quinoline
• IUPAC传统名: 7-methoxy-4-({6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl}methoxy)quinoline

产品登记号

• CAS号: 1002304-34-8

产品性质

• 作用靶点: c-Met
• 成盐信息: Free Base
• 保存条件: -20°C

产品详细信息

详细说明 (English)

Research Area

• Description: Solid tumours

Biological Activity

• Description: AMG-208 is a highly selective c-Met inhibitor with IC50 of 9.3 nM.
• Targets: c-Met
• IC50: 9.3 nM ^[1]
• In Vitro: AMG-208 shows the potent inhibition of kinase c-Met activity with IC50 of 9 nM in a cell-free assay. Besides, AMG-208 treatment also leads to the inhibition of HGF-mediated c-Met phosphorylation in PC3 cells with IC50 of 46 nM. ^[1]Incubation of AMG-208 with rat and human liver microsomes in the presence of NADPH qualitatively yields C6-phenylarene oxidation products as the major metabolites. ^[1] Pre-incubation of AMG-208 with human liver microsomes for 30 minutes shows a potent time-dependent inhibition for CYP3A4 metabolic activity with IC50 of 4.1 μM, which is an eightfold decrease relative to the IC50 (32 μM) without preincubation. ^[2] AMG-208 is identified to be a c-MET and RON dual selective inhibitor. ^[3]
• In Vivo: In male Sprague?Dawley rats, AMG-208 (0.5 mg/kg i.v.) shows a high bioavailability with Cl of 0.37 L/h/kg, V_ss of 0.38 L/kg and T_1/2 of 1 hour, while AMG-208 (2 mg/kg i.v.) shows a bioavailability with AUC_0→∞ of 2517 ng·h/mL and F of 43%, respectively. ^[1]
• Clinical Trials: AMG-208 is currently in Phase I clinical trials in patients with Advanced Solid Tumors.

Protocol

• Protocol: Kinase Assay ^[1]
• In Vitro Kinase Assay: IC50 measurements versus c-Met kinase and its mutants are determined using homogenous time-resolved fluorescence (HTRF) assays. AMG-208 is tested in a 10-point dose-response curve for each enzyme using an ATP concentration of two-thirds K_m for each. Most assays consists of enzyme mixed with kinase reaction buffer [20 mM Tris-HCl (pH 7.5), 10 mM MgCl₂, 5 mM MnCl₂, 100 mM NaCl, 1.5 mM EGTA]. A final concentration of 1 mM DTT, 0.2 mM NaVO₄, and 20 μg/mL BSA is added before each assay. For all assays, 5.75 mg/mL streptavidin-allophycocyanin and 0.1125 nM Eu-PT66 are added immediately before the HTRF reaction. Plates are incubated for 30 minutes at room temperature and read on a Discovery instrument Molecules are tested in a 10-point serial dilution for each c-Met construct using an ATP concentration of two thirds Km value that is determined for each enzyme preparation and calculated using the Eadie-Hofstee and Lineweaver-Burke methods.
• Protocol: Animal Study ^[1]
• Animal Models: Male Sprague-Dawley rats
• Formulation: AMG-208 is dissolved in DMSO.
• Doses: ≤2 mg/kg
• Administration: Administered via i.v. and p.o.

References

• References: [1] Albrecht BK, et al. J Med Chem. 2008, 51(10), 2879-2882.
• References: [2] Boezio AA, et al. Bioorg Med Chem Lett. 2009, 19(22), 6307-6312.
• References: [3] Liu X, et al. Trends Mol Med. 2010,16(1), 37-45.

参考文献

• Albrecht BK, et al. J Med Chem. 2008, 51(10), 2879-2882.
• Boezio AA, et al. Bioorg Med Chem Lett. 2009, 19(22), 6307-6312.
• Liu X, et al. Trends Mol Med. 2010,16(1), 37-45.