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VX-745

现货
Catalog No.
A8686
P38α抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,000.00
现货
10mg
¥ 950.00
现货
50mg
¥ 4,340.00
现货

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Background

VX-745 is a first-generation inhibitor of p38αMAPK with IC50 value of 1.0 μM when tested with Werner syndrome dermal fibroblasts [1].

Mammalian mitogen-activated protein (MAP) kinases are serine /threonine kinases and have 4 subfamilies: ERK, JNK, MAPKp38 and ERK5. MAPK pathway plays a pivotal role in transmitting signals from cell membrane to nucleus and also participates in many intracellular signaling pathways that control a wide spectrum of cellular processes (growth, differentiation, stress responses, cancer progression) [2]. MAPKp38 is originally isolated from lipopolysaccharide-stimulated monocytes. And according to the distribution in tissue, regulation of kinase activation and subsequent phosphorylation of downstream substrates, it is divided into four isoforms p38alpha, p38beta, p38gamma and p38delta [3].

VX-745 is an exquisite kinase selectively inhibit p38αMAPK and is regarded as an anti-inflammatory candidate. When tested with PBMCs or whole blood, VX-745 treatment could inhibit the secretion of IL-1β and TNF-α in vitro [4]. In human dermal fibroblast cells, VX-745 treatment blocked p38 signaling to rescue the aging phenotype in Werner syndrome [5].

References:
[1].  Bagley, M.C., et al., Microwave-assisted Ullmann C-S bond formation: synthesis of the P38alpha MAPK clinical candidate VX-745. J Org Chem, 2009. 74(21): p. 8336-42.
[2].  Dent, P., et al., MAPK pathways in radiation responses. Oncogene, 2003. 22(37): p. 5885-96.
[3].  Dominguez, C., D.A. Powers, and N. Tamayo, p38 MAP kinase inhibitors: many are made, but few are chosen. Curr Opin Drug Discov Devel, 2005. 8(4): p. 421-30.
[4].  Duffy, J.P., et al., The Discovery of VX-745: A Novel and Selective p38alpha Kinase Inhibitor. ACS Med Chem Lett, 2011. 2(10): p. 758-63.
[5].  Bagley, M.C., et al., Gram-scale synthesis of the p38alpha MAPK-inhibitor VX-745 for preclinical studies into Werner syndrome. Future Med Chem, 2010. 2(9): p. 1417-27.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt436.27
Cas No.209410-46-8
FormulaC19H9Cl2F2N3OS
Solubility≥21.8mg/mL in DMSO
Chemical Name5-(2,6-dichlorophenyl)-2-(2,4-difluorophenyl)sulfanylpyrimido[1,6-b]pyridazin-6-one
SDFDownload SDF
Canonical SMILESC1=CC(=C(C(=C1)Cl)C2=C3C=CC(=NN3C=NC2=O)SC4=C(C=C(C=C4)F)F)Cl
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

分光光度法偶联酶检测

在含10%甘油,10 mM MgCl2,2.5 mM磷酸烯醇丙酮酸,200 μM NADH,150 μg/mL丙酮酸激酶,50 μg/mL 乳酸脱氢酶以及200 μM EGF受体肽 (KRELVEPLTPSGEAPNQALLR) 的0.1 M HEPES缓冲液(pH 7.5)中,加入15 nM p38α或p38β,再加入溶于DMSO的VX-745,将混合物置于30 °C下孵育10分钟。在p38α和p38β试验中,分别加入100 μM和70 μM ATP开始反应。在340 nm处,测定吸光值的降低值,以监测反应速率。从作为抑制剂浓度的函数的速率数据评估IC50。

细胞实验 [2]:

细胞系

人类骨髓基质细胞 (BMSCs) 和多发性骨髓瘤 (MM) 细胞

制备方法

在DMSO中的溶解度大于21.8 mg/mL。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20 °C可放置数月。

反应条件

60 nM ~ 20 μM;48小时

实验结果

在BMSCs中,VX-745抑制IL-6和VEGF分泌,同时不影响细胞活力。VX-745抑制TNF-α诱导的IL-6分泌。此外,VX-745抑制MM细胞粘附到BMSCs诱导的MM细胞增殖和BMSCs分泌IL-6。上述结果表明,VX-745能抑制骨髓环境中旁分泌MM细胞生长,并克服细胞粘附相关的耐药性。

动物实验 [1]:

动物模型

II型胶原诱导的关节炎 (CIA) 小鼠模型

给药剂量

2.5、5和10 mg/kg;口服给药;每天2次,持续20天

实验结果

在CIA小鼠模型中,VX-745在2.5 mg/kg、5 mg/kg和10 mg/kg的剂量下,使炎症评分分别改善了27%、31%和44%。此外,与溶媒对照组相比,VX-745使组织学评分改善了32 ~ 39%。上述结果表明VX-745对骨质和软骨侵蚀具有保护作用。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Duffy, J.P., et al., The Discovery of VX-745: A Novel and Selective p38alpha Kinase Inhibitor. ACS Med Chem Lett, 2011. 2(10): p. 758-63.

[2]. Hideshima T, Akiyama M, Hayashi T, Richardson P, Schlossman R, Chauhan D, Anderson KC. Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood. 2003 Jan 15;101(2):703-5.

生物活性

描述 VX-745是p38α有效的选择性抑制剂,IC50值为10 nM。
靶点 p38α p38β        
IC50 10 nM 220 nM        

质量控制

化学结构

VX-745