6-{[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}quinoline

• ChemBase编号: 6192
• 分子式: C18H13N7S
• 平均质量: 359.40772
• 单一同位素质量: 359.09531445
• SMILES: c1cc(c2cnn(C)c2)nn2c1nnc2Sc1cc2c(cc1)nccc2
• Canonical SMILES: Cn1ncc(c1)c1ccc2n(n1)c(nn2)Sc1ccc2c(c1)cccn2
• InChI: InChI=1S/C18H13N7S/c1-24-11-13(10-20-24)16-6-7-17-21-22-18(25(17)23-16)26-14-4-5-15-12(9-14)3-2-8-19-15/h2-11H,1H3
• InChIKey: BCZUAADEACICHN-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: 6-{[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}quinoline
• IUPAC传统名: 6-{[6-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}quinoline
• 别名: 6-{[6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}quinoline; SGX-523

登记号

• CAS号: 1022150-57-7
• PubChem SID: 99445055; 160969617
• PubChem CID: 24779724

理论计算性质

JChem

• 质子受体: 5
• 质子供体: 0
• LogD (pH = 5.5): 3.1609778
• LogD (pH = 7.4): 3.183811
• Log P: 3.1841109
• 摩尔折射率: 123.7361 cm^3
• 极化性: 40.324444 Å^3
• 极化表面积: 73.79 Å^2
• 可自由旋转的化学键: 3
• 里宾斯基五规则: true

ALOGPS 2.1

• Log P: 2.94
• LOG S: -4.31
• 溶解度: 1.77e-02 g/l

分子性质

理化性质

• 溶解度: DMSO

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: c-Met

产品相关信息

• 成盐信息: Free Base

详细说明

DrugBank - DB08584

Drug information: experimental

Selleck Chemicals - S1112

Research Area

• Description: Cancer

Biological Activity

• Description: SGX-523 is a selective Met inhibitor with IC50 of 4 nM.
• Targets: Met
• IC50: 4 nM ^[1]
• In Vitro: SGX-523 belongs to the class of c-Met/hepatocyte growth factor receptor (HGFR) tyrosine kinase inhibitors. SGX-523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for its selectivity. SGX523 potently inhibits the purified MET catalytic domain but not the closely related receptor tyrosine kinase RON. SGX523 indicates ATP-competitive inhibition with higher apparent affinity for the less active, unphosphorylated form of MET [MET-KD(0P), with a Ki of 2.7 nM] versus the more active phospho-enzyme [MET-KD(3P), with a Ki of 23 nM], a phenomenon consistent with preferential binding to an inactive enzyme conformation. SGX523 inhibits MET-mediated signaling, cell proliferation and cell migration at nanomolar concentrations but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concentrations.^[1]
• In Vivo: SGX523 significantly retards the growth of preestablished GTL16 tumors when administered orally at doses of ≥10 mg/kg twice daily. SGX523 potently inhibits U87MG tumor growth; at 30 mg/kg dosed twice daily, SGX523 leads to clear regression of U87MG tumors. SGX523, dosed twice daily at 30 mg/kg, also retards the growth of H441 tumors with concomitant reduction in tumor MET autophosphorylation levels. SGX523 inhibition of MET in vivo is associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma, lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. ^[1]
• Clinical Trials: A phase I clinical trial of SGX523 for the treatment of advanced cancer has been completed.

Protocol

• Protocol: Kinase Assay ^[1]
• Kinase assays: Initial rate constants are measured at 21 °C in the presence of 100 mM HEPES (pH 7.5), 0.3 mg/mL poly(Glu-Tyr) peptide substrate, 10 mM MgCl₂, 1 mg/mL bovine serum albumin, 5% DMSO, 20 nM MET-KD and various concentrations of ATP and SGX523. Total reaction volumes (20 μL) are quenched with 20 μL Kinase-Glo detection buffer. Luminescence is detected in a plate-reading luminometer and the results are analyzed by nonlinear regression.
• Protocol: Cell Assay ^[1]
• Cell Lines: MDCK cells
• Concentrations: 200 nM
• Incubation Time: 18 hours
• Methods: MDCK cells are seeded at 1 × 10^3 per well in a 24-well plate and incubated at 37 °C in 5% CO₂ for 1 week in MEM and 10% fetal bovine serum. HGF (90 ng/mL) and various concentrations of SGX523 are added and the cells are incubated for another 18 hours (37 °C, 5% CO₂ humidified incubator) and visualized. A549 cells are plated in 12-well plates (6 × 10^4 per well) and incubated to confluence to investigate cell migration. A channel is introduced into the monolayers by scratching with a pipette tip. Various dilutions of compound are added in starve medium in the presence and absence of HGF (90 ng/mL).The wells are checked for cell migration after twenty-four hours.
• Protocol: Animal Study ^[1]
• Animal Models: GTL16, U87, or H441 xenografts in Harlan nude mice
• Formulation: 0.5% MC 400 with 0.05% Tween 80
• Doses: 60 mg/kg
• Administration: Oral gavage

References

• References: [1] Buchanan SG, et al. Mol Cancer Ther, 2009, 8(12), 3181-3190.

参考文献

• Buchanan SG, et al. Mol Cancer Ther, 2009, 8(12), 3181-3190.