VX-809
(Synonyms: 鲁玛卡托; VX-809; VRT 826809) 目录号 : GC15455
A F508del-CFTR corrector
Cas No.:936727-05-8
Sample solution is provided at 25 µL, 10mM.
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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
| Kinase experiment [1]: | |
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Inhibitory activities |
Lumacaftor(VX-809), succeeded in a Phase III clinical trial, is a cystic fibrosis transmembrane conductance regulator (CFTR) corrector. VX-809 had been shown to increase membrane expression of mutant channels and cell surface density of functional F508del-CFTR in vitro. |
| Cell experiment [2]: | |
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Cell |
Human bronchial epithelial (HBE) cells, F508del-CFBE cells, CF-HBE cells (F508del/F508del) and A549 cells. |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
Expose time: 48 h. |
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Applications |
In human bronchial epithelial (HBE) cells, VX-809 could increase F508del-CFTR Cl secretion, and increase FEV1 by an average of 3-5% in CF patients with homozygous for the F508del-CFTR mutation in combination with VX-770. |
| Human experiment [1]: | |
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Patients model |
Patients with Cystic Fibrosis Homozygous |
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Dosage form |
600 mg once daily or 400 mg every 12 hours |
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Preparation method |
orally administered |
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Applications |
At the plasma membrane, it increased F508del-CFTR levels. Alone or in combination with ivacaftor improved clinical outcome in patients with homozygous for the F508del mutation, Lumacaftor acted an key role in the treatment of biochemical abnormalities in CF. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. The actual solubility may slightly differ with the theoretical value. |
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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) | |
| Cas No. | 936727-05-8 | SDF | |
| 别名 | 鲁玛卡托; VX-809; VRT 826809 | ||
| 化学名 | 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid | ||
| Canonical SMILES | CC1=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 | ||
| 分子式 | C24H18F2N2O5 | 分子量 | 452.41 |
| 溶解度 | ≥ 22.6mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2104 mL | 11.0519 mL | 22.1038 mL |
| 5 mM | 0.4421 mL | 2.2104 mL | 4.4208 mL |
| 10 mM | 0.221 mL | 1.1052 mL | 2.2104 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet