Lumacaftor

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Chemical Structure| 936727-05-8 同义名 : VX-809;VRT 826809;Orkambi;​Lumacaftor
CAS号 : 936727-05-8
货号 : A121674
分子式 : C24H18F2N2O5
纯度 : 98%
分子量 : 452.41
MDL号 : MFCD16659051
存储条件：

Pure form Keep in dark place,Inert atmosphere,Room temperature

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 25 mg/mL(55.26 mM)，配合低频超声，并水浴加热至45℃助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+40% PEG300+water 4 mg/mL clear

PO 0.5% CMC-Na 40 mg/mL suspension

生物活性
靶点

  • CFTR

    F508del-CFTR, EC50:0.1 μM
描述 Cystic fibrosis (CF) is a genetic disorder with the loss of chloride transport due to the defects in CF transmembrane conductance regulator (CFTR) protein. VX-809 is a CFTP corrector that partially increases the delivery of CFTR to cell surface, thereby restoring the function of chloride transportation. It improved the maturation of F508del-CFTR, the most common CFTR mutation, in FRT cells with an EC50 value at 0.1 μM; and increased F508del-CFTR-mediated chloride transport with an EC50 at 0.5 μM. Data from F508del-HEK293 cells showed that incubation with 3 μM VX-809 for 24 hours increased F508del-CFTR exit from the endoplasmic reticulum by 6 folds compared with control cells. Also, cultured F508del-HBE cells treated with 3 μM VX-809 for 48 hours showed 14% higher maximal level of chloride transport compared to normal HBE cells[5]. In a human lung epithelium-derived cell line that was transfected with horseradish peroxidase (HRP)-tagged CFTR (F508-HRP CFBE41o-), cells treated with 2 μM VX-809 at 37C for 24 hours showed 4-fold HRP luminescence signal increase compared to DMSO-treated cells. Similar result was also found in R1070W-HRP CFBE41o- cells with 2.5-fold signal increase after VX-809 treatment at the concentration of 2 μM[6]. A phase 2 study in homozygous CF patients reported that daily intake of 100 and 200 mg VX-809 for 28 days significantly decreased their elevated sweat chloride values[7].
作用机制 VX-809 suppresses the folding defects of transmembrane conductance regulator (CFTR) protein by stabilizing an N-terminal domain in the CFTR that contains membrane-spanning domain 1[8].
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
human CFBE41o cells Function assay Corrector activity at CFTR F508del mutant (unknown origin) expressed in human CFBE41o cells assessed as increase in fully glycosylated protein by western blot analysis 26041577
临床研究
NCT号 适应症或疾病 临床期 招募状态 预计完成时间 地点
NCT03474042 Cystic Fibrosis Phase 2 Completed - Germany ... 展开 >> Study Site II Berlin, Germany Study Site X Dresden, Germany Study Site III Essen, Germany Study Site IV Frankfurt, Germany Study Site I Heidelberg, Germany Study Site V Köln, Germany Study Site VI München, Germany Study Site IX Stuttgart, Germany Study Site VIII Tübingen, Germany 收起 <<
NCT02821130 - Active, not recruiting December 2019 Canada, British Columbia ... 展开 >> UBC James Hogg Research Centre, St. Paul's Hospital Vancouver, British Columbia, Canada, V6Z1Y6 收起 <<
NCT02965326 Cystic Fibrosis Not Applicable Recruiting October 2020 France ... 展开 >> Necker Hospital Recruiting Paris, France, 75014 Contact: SERMET Isabelle, Professor    01 44 49 48 87    isabelle.sermet@nck.aphp.fr    Principal Investigator: SERMET Isabelle, Professor 收起 <<
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.21mL

0.44mL

0.22mL

11.05mL

2.21mL

1.11mL

22.10mL

4.42mL

2.21mL
参考文献

[1]lumacaftor

[2]Van Goor F, Hadida S, 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 Nov 15;108(46):18843-8.

[3]108(46):18843-8.

[4]86(1):42-51.

[5]Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu PA. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18843-8.

[6]Phuan PW, Veit G, Tan J, Roldan A, Finkbeiner WE, Lukacs GL, Verkman AS. Synergy-based small-molecule screen using a human lung epithelial cell line yields ΔF508-CFTR correctors that augment VX-809 maximal efficacy. Mol Pharmacol. 2014 Jul;86(1):42-51.