Ivacaftor (VX-770)

Katalognr.S1144 Batch:S114405

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Tekniska data

Formel

C24H28N2O3
Molekylvikt 392.49 CAS-nr. 873054-44-5
Löslighet (25°C)* In vitro DMSO 78 mg/mL (198.73 mM)
Water Insoluble
Ethanol Insoluble
In Vivo (Tillsätt lösningsmedel till produkten individuellt och i ordning.)
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <1 mg/ml betyder svårlösligt eller olösligt.
* Vänligen notera att Selleck testar lösligheten för alla förbindelser internt, och den faktiska lösligheten kan skilja sig något från publicerade värden. Detta är normalt och beror på små variationer mellan olika partier.
* Rumstempererad frakt (Stabilitetstester visar att denna produkt kan fraktas utan några kylåtgärder.)

Beredning av stamlösningar

Biologisk aktivitet

Beskrivning Ivacaftor (VX-770) är en selektiv potentiator av CFTR som riktar sig mot G551D-CFTR och F508del-CFTR med EC50 på 100 nM respektive 25 nM i fisherråttsköldkörtelceller.
Mål
F508del-CFTR
(Fisher rat thyroid cells)		 G551D-CFTR
(Fisher rat thyroid cells)
25 nM(EC50) 100 nM(EC50)
In vitro

Ivacaftor (VX-770) (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, this compound increases the open probability (Po) of G551D-, F508del-, and wild-type CFTR by ~6-fold, ~5-fold and ~2-fold, respectively, indicating that it 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 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, it 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, this compound inhibits excessive ENaC-mediated Na+ and fluid absorption with an IC50 of 43 nM, and decreases the response, resulting in an increase in the surface fluid and cilia beat frequency (CBF) in G551D/F508del HBE.

Egenskaper Den första potenta och oralt tillgängliga CFTR-potentiatorn som går in i kliniska studier på människor.

Protokoll (från referens)

Kinasanalys:

[1]
  • Ussingkammarinspelningar

    Effekten av Ivacaftor (VX-770) på CFTR-medierad Cl--sekretion karakteriseras genom att mäta den CFTR-medierade IT i kammare med rekombinanta Fisher-råttsköldkörtelceller (FRT) som uttrycker G551D eller F508del CFTR. Celler odlas på Costar Snapwell-cellodlingsinsatser som hålls vid 37 °C före inspelning. Cellodlingsinsatserna monteras i en Ussingkammare för att registrera IT i spänningsklämningsläget (Vhold = 0 mV). För FRT-celler etableras basolaterala membranet som en basolateral till apikal Cl--gradient. Den basolaterala badlösningen innehåller 135 mM NaCl, 1,2 mM CaCl2, 1,2 mM MgCl2, 2,4 mM K2HPO4, 0,6 mM KHPO4, 10 mM N-2-hydroxietyldipiperazin-N
Cellanalys:

[2]
  • Cellinjer

    FRT and NIH 3T3 cells

  • Koncentrationer

    100/25 nM

  • Inkubationstid

    24 h

  • Metod

    Cells were treated with various concentrations of Ivacaftor (VX-770).
Djurstudie:

[2]
  • Djurmodeller

    Male Sprague-Dawley rats

  • Doseringar

    3 mg/kg

  • Administrering

    i.v.

Referenser

  • https://pubmed.ncbi.nlm.nih.gov/19846789/
  • https://pubmed.ncbi.nlm.nih.gov/25441013/

Kundvalidering av produkt

(A) CFTR Western blot of normal (NL) and CF HBE cultures treated with VX-809 (5 uM) ± VX-770 (5 uM) for 48 hours. “*” indicates the mature, complex glycosylated form of CFTR, band C; “•” indicates the immature band B. (B) Turnover of rescued ΔF508 in BHK-21 cells. ΔF508 was rescued at 27°C in the presence of VX-809 ± VX-770 for 24 hours. After adding cycloheximide (200 ug/ml, 37°C), cells were lysed at the indicated times and analyzed by Western blotting.

Data från [ Sci Transl Med , 2014 , 6(246), 246ra96 ]

<p> </p><p>(A) Representative traces of Ca2+ mobilization induced by 100 μm of OAG after modulation of CFTR activity with 10 μm VX-770. (B) Histograms show normalized AUC corresponding to Ca2+ mobilization induced by 100 μm OAG (n, number of cells recorded/N, number of cell passages).</p>

,

<p> </p><p>(C) Representative traces of iodide efflux curves after CFTR stimulation with 10 μm VX-770 or 100μm OAG. (D) Histograms show the mean relative rate of CFTR activity for the experimental condition indicated below each bar (n = 4).</p>

,

Treatment with DF508 CFTR correcting drugs (VX-770 and VX-809, 10 lM) partially redistributed F-actin in the submembrane compartment as also shown by the two small membrane peaks in the quantification graph. Treatment with PP2 (1 lM) alone or in combination with VX-770 and VX-809 completely recovered the actin distribution in DF508-chol similar to Control-chol. Phalloidin fluorescence intensity confirms the presence of membrane sharper peaks that reach intensity values comparable to Control-chol. Abbreviations: A.U, arbitrary units; chol, cholangiocytes.

Data från [ , , Hepatology, 2018, 67(3):972-988 ]

Sellecks Ivacaftor (VX-770) Har citerats av 298 Publikationer

Identification of small molecules that enhance aminoglycoside-mediated suppression of CFTR and NF1 nonsense mutations [ Mol Ther Oncol, 2026, 34(2):201173] PubMed: 41939791
Altered functional interactions between CFTR disease mutants ΔF508 and G551D and the protein kinase A catalytic subunit [ J Physiol, 2026, 604(8):3344-3362] PubMed: 41920076
Investigation of HE4 expression concerning epithelial-mesenchymal transition (EMT) in cystic fibrosis epithelial cells [ J Cyst Fibros, 2026, S1569-1993(26)00086-X] PubMed: 41936498
Functional, Cohort-Level Assessment of CFTR Modulator Responses Using Biobanked Nasal Epithelial Cells from Individuals with Cystic Fibrosis [ J Pers Med, 2026, 16(1)51] PubMed: 41590543
CFTR rescue in W1282X cystic fibrosis patient-derived intestinal organoids (PDIOs) mediated by translational readthrough-inducing drugs (TRIDs) [ Genet Med Open, 2026, 4:103472] PubMed: 41492359
ACE-tRNAs are a platform technology for suppressing nonsense mutations that cause cystic fibrosis [ Nucleic Acids Res, 2025, 53(13)gkaf675] PubMed: 40650978
Transcriptomic and functional responses of the cystic fibrosis airway epithelium to CFTR modulator therapy [ JCI Insight, 2025, 10(21)e196018] PubMed: 41212059
Endometrium-derived organoids from cystic fibrosis patients and mice as new models to study disease-associated endometrial pathobiology [ Cell Mol Life Sci, 2025, 82(1):109] PubMed: 40074868
CFTR negatively reprograms Th2 cell responses, and CFTR potentiation restrains allergic airway inflammation [ JCI Insight, 2025, 10(9)e191098] PubMed: 40131363
Human induced pluripotent stem cells for in vitro modeling of impaired mucociliary clearance in cystic fibrosis lung disease [ Stem Cell Res Ther, 2025, 16(1):573] PubMed: 41116195

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