|N-(5-((6,7-二甲氧基喹啉-4-基)氧基)吡啶-2-基)-2,5-二氧代-1-苯基-1,2,5,6,7,8-六氢喹啉-3-甲酰胺|CsnPharm

CAS No.: 1646839-59-9

N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Catalog No. CSN25618

Synonyms: ONO-7475

ONO-7475 is a potent and selective inhibitor of active novel Axl/Mer tyrosine kinase with IC50 values of 0.7nM and 1nM, respectively. It potently arrested growth and induced apoptosis in acute myeloid leukemia with internal tandem duplication mutation of FMS-like tyrosine kinase 3.

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实验方案

技术信息

生物活性

描述Anexelekto (AXL) is a receptor tyrosine kinase (RTK) of the TAM (Tyro3, AXL, and MER) family. Activation of AXL by growth arrest specific 6 (GAS6) induces diverse survival cascades. Recent studies have revealed that AXL regulates survival signaling in many cancers, including leukemia. ONO-7475 is an inhibitor with high specificity for AXL and MER tyrosine kinase with IC₅₀ values of 0.7 nM and 1.0 nM, respectively. In MOLM13 and MV4;11 cells, ONO-7475 (10 nM; 48 h) significantly reduced cell viability by >50% and induced apoptosis. After 72 hours, 10 nM ONO-7475 nearly eliminated all viable MOLM13 cells with >70% of cells becoming apoptotic. MOLM13 cells in monoculture or in co-culture with MSC (mesenchymal stromal cells) were incubated for 72 hours with vehicle or ONO-7475. The drug potently induced apoptosis and nearly eliminated the AML cells in monoculture. While MSC protected the AML cells from the inhibitor, treatment with a higher dose of drug abrogated most of this effect (50 nM ONO-7475). Low dose ONO-7475 (5 nM) suppressed DNA synthesis in MOLM13 and MV4;11 cells by >2-fold. ONO-7475 potently induced G0/G1 arrest in both cell lines. MOLM13 and MV4;11 were incubated with varying doses of ONO-7475 for 24 hours, ONO-7475 potently suppressed both Cyclin B1 and CDK1 in both cell lines even at a low dose (10 nM). Moreover, AXL is known to induce ERK, and ERK is a positive regulator of MCL-1. ONO-7475 reduced ERK phosphorylation (~50% at 10 nM) and suppressed MCL-1 (>80% at 10 nM) in MOLM13 cells. In a human AML xenograft model, mice given feed with 0.004% ONO-7475 (0.004% is roughly 6 mg/kg daily consumption of drug) exhibited significantly longer median survival compared to mice given control feed. On Day 14, three out of five of the mice given food containing ONO-7475 exhibited reduced leukemic burden compared to the mice which were fed control food^[1].
参考文献

[1] Ruvolo PP, Ma H, Ruvolo VR, et al. Anexelekto/MER tyrosine kinase inhibitor ONO-7475 arrests growth and kills FMS-like tyrosine kinase 3-internal tandem duplication mutant acute myeloid leukemia cells by diverse mechanisms. Haematologica. 2017;102(12):2048-2057

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 1.7775 mL
- 8.8877 mL
- 17.7755 mL
- 5 mM
- 0.3555 mL
- 1.7775 mL
- 3.5551 mL
- 10 mM
- 0.1778 mL
- 0.8888 mL
- 1.7775 mL

技术信息

CAS号

1646839-59-9

储存条件

粉末: Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C32H26N4O6

运输

蓝冰

分子量

562.57

别名

ONO-7475

溶解度

DMSO	100.0 mg/mL (177.8 mM)
Water	Insoluble
Ethanol	Insoluble

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N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Catalog No. CSN25618

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