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Ivacaftor

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Chemical Structure| 873054-44-5 同义名 : 依伐卡托 (VX-770) ;VX-770
CAS号 : 873054-44-5
货号 : A286566
分子式 : C24H28N2O3
纯度 : 99%+
分子量 : 392.491
MDL号 : MFCD17171361
存储条件：

粉末 Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(127.39 mM)，配合低频超声助溶，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 38 mg/mL suspension

生物活性
描述 Cystic fibrosis transmembrane conductance regulator (CFTR) is a protein kinase A-activated epithelial anion channel that is responsible for salt and fluid transport in multiple organs. Ivacaftor is a potent potentiator of CFTR. It increases forskolin-stimulated CFTR-mediated transepithelial current (IT) with an EC50 of 100 ± 47 nM in G551D-FRT cells. Also in F508del-FRT cells, ivacaftor increased forskolin-stimulated IT with an EC50 of 25 ± 5 nM. In recombinant cells expressing G551D-, F508del-, or wild-type (WT)-CFTR, 10 μM ivacaftor increased their CFTR channel open probability by ~6-fold, ~5-fold and ~2-fold, respectively. Treatment of ivacaftor significantly increased the forskolin-stimulated IT in F508del human bronchial epithelia (HBE) cells with an EC50 of 22 ± 10 nM. G551D/F508del HBE cells treated with 10μM ivacaftor for 5 days showed significant increased cilia beat frequency compared with vehicle-treated controls[1]. In the analysis of ATP-independent activity for WT-CFTR, 200 nM ivacaftor increased the activity by 2-fold, as determined by the ratio of post washout ATP-independent current to the robust ATP-induced current[2]. The bilayer studies of WT-CFTR showed that the open probability of CFTR channel treated with both 1 mM Mg-ATP and 2 μM ivacaftor was approximately twice that measured in the presence of Mg-ATP alone. The treatment of 10 μM ivacaftor on liposomes containing phosphorylated F508del-CFTR or phosphorylated G551D-CFTR increased iodide-mediated flux in the presence of 1 mM Mg-ATP[3].
作用机制 Ivacaftor potentiates CFTR function by increasing the open time of WT-CFTR, stabilizing a post-hydrolytic open state, thereby promoting decoupling between the gating cycle and ATP hydrolysis cycle[2].
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
CFBE41o- 10 µM Function Assay induces robust increases in anion transport 22768130
HBE 10 μM Function Assay 10 min augments CFTR-dependent ion transport  24106801
HBE 10 µM Function Assay augments CFTR-dependent anion transport activity 22768130
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
NCT03525548 Cystic Fibrosis Phase 3 Active, not recruiting March 2019 -
NCT03447249 Cystic Fibrosis Phase 3 Active, not recruiting April 16, 2019 -
NCT03525574 Cystic Fibrosis Phase 3 Enrolling by invitation June 2021 -
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.55mL

0.51mL

0.25mL

12.74mL

2.55mL

1.27mL

25.48mL

5.10mL

2.55mL
参考文献

[1]Van Goor F, Hadida S, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009;106(44):18825-30.

[2]Jih KY, Hwang TC. Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle. Proc Natl Acad Sci U S A. 2013;110(11):4404-9.

[3]Eckford PD, Li C, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. J Biol Chem. 2012;287(44):36639-49.