Ivacaftor (VX-770)

Ivacaftor (VX-770) is a potentiator of CFTR targeting G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM, respectively.

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Ivacaftor (VX-770) Chemical Structure

Ivacaftor (VX-770) Chemical Structure
Molecular Weight: 392.49

Validation & Quality Control

Customer Reviews(2)

Quality Control & MSDS

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Product Description

Biological Activity

Description Ivacaftor (VX-770) is a potentiator of CFTR targeting G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM, respectively.
Targets F508del-CFTR [1] G551D-CFTR [1]
IC50 25 nM(EC50) 100 nM(EC50)
In vitro 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]
In vivo
Features The first potent and orally available CFTR potentiator to enter human clinical trials.

Protocol(Only for Reference)

Kinase Assay: [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.
1

References

[1] Van Goor F, et al. Proc Natl Acad Sci U S A, 2009, 106(44), 18825-18830.

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01784419 Recruiting Cystic Fibrosis University of California, San Francisco 2013-10
NCT01946412 Enrolling by invitation Cystic Fibrosis Vertex Pharmaceuticals Incorporated|Cystic Fibrosis Foundation 2013-12 Phase 3
NCT02015507 Completed Cystic Fibrosis Vertex Pharmaceuticals Incorporated 2014-01 Phase 1
NCT02039986 Recruiting Cystic Fibrosis Related Diabetes|Cystic Fibrosis Children's Hospital of Philadelphia 2014-01
NCT02070744 Recruiting Cystic Fibrosis Vertex Pharmaceuticals Incorporated 2014-03 Phase 2

Chemical Information

Download Ivacaftor (VX-770) SDF
Molecular Weight (MW) 392.49
Formula

C24H28N2O3

CAS No. 873054-44-5
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 78 mg/mL (198 mM)
Water <1 mg/mL (<1 mM)
Ethanol <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.
Chemical Name N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

Research Area

Customer Reviews (2)


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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)

Product Citations (4)

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