Ivacaftor (VX-770)

Ivacaftor (VX-770)は、G551D-CFTRとF508del-CFTRを目標としている嚢胞性線維症膜内外コンダクタンス監査機関(CFTR)の強化剤で、EC50 がそれぞれ 100 nM と 25 nMです。

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Ivacaftor (VX-770) 化学構造
分子量: 392.49

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Quality Control & MSDS

製品説明

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製品の説明

生物活性

製品説明 Ivacaftor (VX-770)は、G551D-CFTRとF508del-CFTRを目標としている嚢胞性線維症膜内外コンダクタンス監査機関(CFTR)の強化剤で、EC50 がそれぞれ 100 nM と 25 nMです。
ターゲット G551D-CFTR F508del-CFTR
IC50 100 nM 25 nM [1]
In vitro試験 Ivacaftor (10 μM) significantly increases the forskolin-stimulated Cl- secretion (IT) by ~4-fold with an EC50 of 100 nM in the recombinant Fisher rat thyroid (FRT) cells expressing G551D gating mutation of CFTR, and by ~6-fold with an EC50 of 25 nM in the recombinant cells expressing temperature-corrected F508del processing mutation of CFTR. Consistent with the increases in the forskolin-stimulated IT, Ivacaftor (10 μM) increases the open probability (Po) of G551D-, F508del-, and wild-type CFTR by ~6-fold, ~5-fold and ~2-fold, respectively, indicating that Ivacaftor acts directly on CFTR to increase its gating activity. In primary cultured human CF bronchial epithelia (HBE) carrying the G551D and F508del CFTR mutations, Ivacaftor (10 μM) potently increases the forskolin-stimulated IT by ~10-fold from 5% to a maximum level of 48% of that measured in non-CF HBE, with an EC50 of 236 nM displaying ~70-fold more potency compared with the commonly used CFTR potentiator genistein, which has an EC50 of 16 μM. In HBE with F508del homozygous CFTR, Ivacaftor causes a significant increase in the forskolin-stimulated IT with an EC50 of 22 nM, to a less extent from 4% to 16% of non-CF HBE compared with the effect in G551D/F508del HBE. Due to CFTR potentiation, Ivacaftor inhibits excessive ENaC-mediated Na+ and fluid absorption with an IC50 of 43 nM, and decreases the amiloride response, resulting in an increase in the surface fluid and cilia beat frequency (CBF) in G551D/F508del HBE. [1]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
HBE  Mlr5SpVv[3Srb36gRZN{[Xl? NH7IUmQyOCEQvF2= NIf1enQyOCCvaX6= NWjNUJNI[XWpbXXueJMhS0[WUj3k[ZBmdmSnboSgbY9vKHS{YX7zdI9zfMLi NEDlW5kzPDFyNkiwNS=>
CFBE41o- MU\GeY5kfGmxbjDBd5NigQ>? MUixNEDDvU1? M3;tWolv\HWlZYOgdo9jfXO2IHnuZ5Jm[XOnczDpckBidmmxbjD0doFve3CxcoS= Mo\5NlI4PjhzM{C=
HBE  MVjGeY5kfGmxbjDBd5NigQ>? MUSxNEDDvU1? NF;mWpdifWevZX70d{BETlSULXTldIVv\GWwdDDhcolwdiC2cnHud5BwenRiYXP0bZZqfHl? M3zVfVIzPzZ6MUOw
HBE  MmHYSpVv[3Srb36gRZN{[Xl? NY\reZJzOTBiwsXN M4\Sd|I1KGh? NGr3OIRqdmS3Y3XzJIEhdW:mZYP0JIJ2fCC|aXfubYZq[2GwdDDpcoNz\WG|ZTDpckBCW0xiZHXweIg> M3LWWFIzPzZ6MUOw
HBE  MlHuSpVv[3Srb36gRZN{[Xl? M{GxRlExKML3TR?= MULwc5RmdnSrYYTld{BETlSULXTldIVv\GWwdDDJd4MtKHKnZ3Hy[Ixme3Nib3[gdJJqd3JiYXTtbY5qe3S{YYTpc44hd2ZiQ2PF M{nXcFIzPzZ6MUOw
HBE  Mof4SpVv[3Srb36gRZN{[Xl? MnHiNVAhyrWP Moj6dIFzfGmjbHz5JJJme3SxcnXzJIRmeGyndHnvckBw\iCDU1yg[IVxfGhiaX6gR3NGKHS{ZXH0[YQhdW:wb3zhfYVzew>? NVHwfHNROjJ5NkixN|A>

... Click to View More Cell Line Experimental Data

In vivo試験
臨床試験 A Phase III study of Ivacaftor in cystic fibrosis subjects age 6 to 11 with the G551D mutation has been completed.
特集 The first potent and orally available CFTR potentiator to enter human clinical trials.

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Ussing Chamber Recordings The effect of Ivacaftor on CFTR-mediated Cl- secretion is characterized by measuring the CFTR-mediated IT in chambers using recombinant Fisher rat thyroid (FRT) cells expressing G551D, or F508del CFTR. Cells are grown on Costar Snapwell cell culture inserts maintained at 37 °C before recording. The cell culture inserts are mounted into an Ussing chamber to record IT in the voltage-clamp mode (Vhold = 0 mV). For FRT cells, the basolateral membrane is permeabilized with 360 μg/mL Nystatin and a basolateral to apical Cl- gradient is established. The basolateral bath solution contains 135 mM NaCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 2.4 mM K2HPO4, 0.6 mM KHPO4, 10 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (Hepes), and 10 mM dextrose (titrated to pH 7.4 with NaOH). The apical NaCl is replaced by equimolar Na+ gluconate (titrated to pH 7.4 with NaOH). The addition of a maximally effective concentration of forskolin (10 μM) is used to stimulate IT in the presence of various concentrations of Ivacaftor. All recordings are digitally acquired using Acquire and Analyze software. EC50 values are determined from the concentration-response curve of the increase in forskolin-stimulated IT after application of Ivacaftor.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Ivacaftor (VX-770) SDF
分子量 392.49
化学式

C24H28N2O3

CAS No. 873054-44-5
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 78 mg/mL (198.73 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

カスタマーフィードバック (3)


Click to enlarge
Rating
Source Sci Transl Med, 2014, 6(246), 246ra96. Ivacaftor (VX-770) purchased from Selleck
Method Western blot
Cell Lines HBE, BHK-21 cells
Concentrations 5 uM
Incubation Time 24, 48 h
Results Treatment with VX-809 alone resulted in the formation of a modest amount of mature band C in CF HBE cultures, which was not present in vehicle- or VX-770-treated CF cells (A). The turnover rate of rescued ΔF508 CFTR band C increased, and the half-life accordingly decreased by ~2.5-fold in the presence of VX-770, whereas the decrease in band B levels was not affected by the presence of VX-770 (B).

Click to enlarge
Rating
Source Ivacaftor (VX-770) purchased from Selleck
Method Calcium signal recording
Cell Lines CHO-G551D cells
Concentrations 10 μM
Incubation Time
Results VX-770 reduced OAG Ca2+ influx ( Fig . A) by almost 70% whereas adding GPinh 5a to VX-770 increases OAG Ca2+ influx compared to VX-770 alone ( Fig. B).

Click to enlarge
Rating
Source Ivacaftor (VX-770) purchased from Selleck
Method Iodide efflux
Cell Lines CHO-G551D cells
Concentrations 10 μM
Incubation Time 0-8 min
Results The iodide efflux showed that VX-770 activates G551 D- CFTR channel and that OAG + VX-770 increased G551 D- CFTR activity by 58% ( Fig. C, D)

文献中の引用 (9)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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