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VX-809

现货
Catalog No.
A8351
CFTR调节剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,100.00
现货
5mg
¥ 1,050.00
现货
10mg
¥ 1,680.00
现货
50mg
¥ 4,660.00
现货

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Background

VX-809 is a CFTR corrector that partially restores the function of F508del-CFTR. In Fischer rat thyroid (FRT) cells, it increases F508del-CFTR maturation at EC50 of 0.1 μM, and elevates F508del-CFTR–mediated chloride transport at EC50 of 0.5 μM [1]. It has no effect of other ion channels (hERG), transporter (P-gp) and disease-causing mislocalized proteins (α1-antitrypsin Z mutant) [1]. VX-809 stabilizes N-terminal fragment of CFTR that contain MSD1 by altering its protein conformation [2, 3].

Homozygous F508del-CFTR is the most common mutation in cystic fibrosis (CF) patients, accounting for 66–70% of CF cases worldwide. In cultured human bronchial epithelial cells that are homozygous for F508del, VX-809 restored the CFTR function and improved chloride and fluid Transport [1]. The combination of CFTR potentiators and VX-809 further improved the function of F508del-CFTR [4].

VX-809 has been tested in several clinical trials. Although it had minimal benefit to F508del-CFTR homozygous patients as a monotherapy [4], the result of Phase 2 study of VX-809 and KALYDECO combination showed significant improvements in lung function in CF patients with homozygous F508del-CFTR [5]. VX-809 is currently under investigation in two phase 3 trials.

References:
[1]Van Goor F, Hadida S, Grootenhuis PD et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A 2011; 108: 18843-18848.[2] Ren HY, Grove DE, De La Rosa O et al. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol Biol Cell 2013; 24: 3016-3024.[3]Loo TW, Bartlett MC, Clarke DM. Corrector VX-809 stabilizes the first transmembrane domain of CFTR. Biochem Pharmacol 2013; 86: 612-619.[4]Clancy JP, Rowe SM, Accurso FJ et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 2012; 67: 12-18.[5]http://investors.vrtx.com/releasedetail.cfm?releaseid=687394

Chemical Properties

StorageStore at -20°C
M.Wt452.41
Cas No.936727-05-8
FormulaC24H18F2N2O5
SynonymsVX 809; VX809; Lumacaftor; VRT 826809
Solubility≥22.6mg/mL in DMSO
Chemical Name3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid
SDFDownload SDF
Canonical SMILESCC1=C(N=C(C=C1)NC(=O)C2(CC2)C3=CC4=C(C=C3)OC(O4)(F)F)C5=CC(=CC=C5)C(=O)O
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]:

抑制活性

Lumacaftor(VX-809)已进入III期临床试验,是囊性纤维化跨膜传导调节因子(CFTR)的校正物。在体外实验中,VX-809增加突变通道的膜表达和功能性F508del-CFTR的细胞表面密度。

细胞实验: [2]

细胞系

人支气管上皮(HBE)细胞、F508del-CFBE细胞、CF-HBE细胞(F508del/F508del)和A549细胞。

制备方法

该化合物在DMSO中的溶解度大于10 mM,若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃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℃可放置数月。

反应条件

48 h

实验结果

在人支气管上皮(HBE)细胞中,VX-809可以增加F508del-CFTR C1的分泌,在F508del-CFTR突变的纯合CF患者中,VX-809与VX-770组合给药将FEV1平均增加3?5%。

临床试验[1]:

患者

囊性纤维化纯合患者

给药剂量

600 mg每日一次;每12小时400 mg

给药方式

口服

实验结果

在质膜上,它增加F508del-CFTR水平。单独或与ivacaftor组合改善了F508del突变的纯合子患者的临床结果,Lumacaftor在治疗CF的生化异常中起关键作用。

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]. Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015 Jul 16;373(3):220-31.

[2] Stanton BA, Coutermarsh B, Barnaby R, et al. Pseudomonas aeruginosa Reduces VX-809 Stimulated F508del-CFTR Chloride Secretion by Airway Epithelial Cells. PLoS One. 2015 May 27;10(5)

生物活性

描述 VX-809 (Lumacaftor)通过促进突变型CFTR(F508del-CFTR)的成熟,从而纠正囊性纤维化中常见的CFTR突变,EC50值为0.1 μM。
靶点 CFTR          
IC50 0.1 μM          

质量控制

化学结构

VX-809

相关生物数据

VX-809

相关生物数据

VX-809