VX-809 (Lumacaftor)

Catalog No.S1565 Synonyms: VRT 826809

VX-809 (Lumacaftor) Chemical Structure

Molecular Weight(MW): 452.41

VX-809 (Lumacaftor) acts to correct CFTR mutations common in cystic fibrosis by increasing mutant CFTR (F508del-CFTR) maturation,EC50 of 0.1 μM in fisher rat thyroid cells. Phase 3.

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In DMSO USD 340 In stock
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USD 970 In stock
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3 Customer Reviews

  • △F508CFTR diffusion is increased by different correction mechanisms. A, example trajectories from MDCK cell lines for wtCFTR (black) and △F508CFTR rescued by VX-809 treatment in the absence (red) and presence (blue ) of mCh-CFTR-C. B, summary graph for wtCFTR, r△F508CFTR and CFTR△PDZ diffusion in VX-809-treated and control MDCK cell lines. C, example trajectories for MDCK cells transiently expressing 3FLAG-tagged wtCFTR(black), △F508CFTR rescued by VX-809 (red), CFTR△PDZ ( blue ), and △F508CFTR△PDZ rescued by VX-809 (green). D, summary graph for CFTR dif- fusion in VX-809-treated MDCK transiently transfected with 3FLAG-tagged CFTR constructs. E, example trajectories from MDCK cell lines stably expressing wtCFTR ( left ) and △F508CFTR ( right ) treated with thapsigargin ( black)or CoPo-22 (red) or transiently expressing GFP-GRASP55 (blue ). F, graphs for △F508CFTR ( top ) and wtCFTR (bottom) diffusion in MDCK cell lines treated with thapsigargin or CoPo-22 or transiently expressing GFP-GRASP55. For reference, median and interquartile values for wtCFTR diffusive range are shown by dashed lines(bar 1, top ). G, GFP-GRASP55 is Golgi-localized by immunocytochemical analysis (scale bar, 10 μm). Scale bar in A (500 nm) refers to all trajectories. In panels Band D, statistically significant differences in populations are shown (*, p<0.001). SPT data for MDCK cell lines was derived from 140 –788 trajectories and for transiently transfected MDCK cells from 131–298 trajectories.

    J Biol Chem 2012 287, 43630-8. VX-809 (Lumacaftor) purchased from Selleck.

     

    VX809 inceases the expression of DF508 CFTR in oocytes.  Oocytes injected with DF508 CFTR and b-adrenergic receptor RNAs were incubated at 17oC for 3 days with and without 5 μM VX809.  The conductance at the reversal potential (gCl at Vm = Erev) was assayed using two-electrode-voltage clamp. Oocytes were placed in experimental chambers and perfused with standard Frog Ringer's at room temperature where the conductance was monitored as a function of time. The conductance was near zero before stimulation using a cocktail containing 10 μM isoproterenol and 1 μM 3-isobutyl-1-methylxanthine (hatched bar).  At steady state, conductance of oocytes treated with 5 μM VX809 ("x" symbols in panel A and white bar in panel B) was significantly larger than that of untreated oocytes ("+" symbols in panel A and black bar in panel B).  Towards the end of the experiments, oocytes were exposed to 10 μM CFTR-172 to verify that the conductance was due to CFTR chloride channels. 

    Xuehong Liu of Oregon Health & Science University. VX-809 (Lumacaftor) purchased from Selleck.

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    Figure 7. Using chamber experiments demonstrating that TGF- β1 inhibits functional rescue of △ F508-CFTR in CF-HBE cells. Representative recordings ( A&B) demonstrating that VX-809 and CF-106951 partially rescued the CFTRinh -172 sensitive I sc compared to vehicle control (Vehicle). VX-809 (10 μM), CF-106951 (10 μM) or vehicle control (DMSO) was added to the basolateral medium for 24 h. The final concentration of DMSO was ,0.1%. Experiments were repeated at least 3 times in CF-HBE cells from 3 different donors. In subsequent experiments, corrector VX-809 ( C&D) or CF-106951 ( E&F ) was used for 24 h to rescue the CFTRinh-172 sensitive Isc. Subsequently, TGF- β1 (15 ng/ml) or vehicle control (CTRL) was added with fresh VX-809 or CF-106951 to the basolateral medium for 24 h. Monolayers were bathed in Ringer’s solution in the presence of amiloride (10 μM). TGF-β1 decreased the CFTRinh-172 sensitive Isc rescued by either VX-809 or CF-106951.

    VX-809 (Lumacaftor) purchased from Selleck.

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Biological Activity

Description VX-809 (Lumacaftor) acts to correct CFTR mutations common in cystic fibrosis by increasing mutant CFTR (F508del-CFTR) maturation,EC50 of 0.1 μM in fisher rat thyroid cells. Phase 3.
Features Higher specificity and efficacy relative to other CFTR defect drugs.
Targets
F508del-CFTR [1]
(Fisher rat thyroid cells)
0.1 μM(EC50)
In vitro

VX-809 acts at the level of the ER to allow a fraction of the F508del-CFTR to adopt a properly folded form, to exit the ER and mobilize to the cell surface for normal functioning. In Fischer rat thyroid (FRT) cells expressing F508del-CFTR, VX-809 treatment significantly improves F508del-CFTR maturation by 7.1 fold with an EC50 of 0.1 μM, and enhances F508del-CFTR-mediated chloride transport by approximately 5 fold with EC50 of 0.5 μM, while VRT-768 has higher EC50 values of 7.9 μM and 16 μM, respectively. In HEK-293 cells expressing F508del-CFTR, VX-809 (3 μM) treatment increases F508del-CFTR exit from the ER by 6 fold, reaching levels comparable to 34% of CFTR. In primary human bronchial epithelial (HBE) cells with F508del-CFTR mutation, VX-809 increases CFTR maturation and enhances chloride secretion with EC50 of 350 nM and 81 nM, respectively, more efficacious than Corr-4a and VRT-325. F508del-CFTR corrected by VX-809 exhibits single-channel open probability of 0.39 similar to normal CFTR of 0.40. Unlike VX-770, VX-809 is not a CFTR potentiator, as acute addition of VX-809 has no effect on F508del-CFTR function. In contrast to VRT-325 and Corr-4a, VX-809 does not improve the processing of the normal or mutant forms of hERG or P-gp, as well as other disease-causing mislocalized proteins, including α1-antitrypsin Z mutant (E342K-α1-AT) or N370S-β-glucosidase, suggesting that VX-809 is specific for CFTR. VX-809 in combination with VRT-325 or Corr-4a has additive effect on CFTR-mediated chloride transport in cultured F508del-HBE. [1]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human CFBE41o cells M4DsT2Z2dmO2aX;uJIF{e2G7 NIjyZVVEd3K{ZXP0c5Ih[WO2aY\peJkh[XRiQ1\UVkBHPTB6ZHXsJI12fGGwdDCoeY5sdm:5bjDvdolocW5rIHX4dJJme3OnZDDpckBpfW2jbjDDSmJGPDGxIHPlcIx{KGG|c3Xzd4VlKGG|IHnuZ5Jm[XOnIHnuJIZ2dGy7IHfsfYNwe3muYYTl[EBxem:2ZXnuJIJ6KHenc4Tldo4h[myxdDDhcoFtgXOrcx?= NFPzVGQzPjB2MUW3Oy=>

... Click to View More Cell Line Experimental Data

Protocol

Kinase Assay:[1]
+ Expand

F508del-CFTR maturation:

Fischer rat thyroid (FRT) cells stably expressing F508del-CFTR are treated with increasing concentrations of VX-809 for 48 hours. After incubation, cells are harvested in ice-cold D-PBS solution (without calcium and magnesium) and pelleted at 1,000 × g at 4 °C. Cell pellets are lysed in 1% Nonidet P-40, 0.5% sodium deoxycholate, 200 mM NaCl, 10 mM Tris, pH 7.8, and 1 mM EDTA plus protease inhibitor mixture (1:250) for 30 minutes on ice. Lysates are spun for 10 minutes at 10,000 × g at 4 °C to pellet nuclei and insoluble material. Approximately 12 μg total protein is heated in Laemmli buffer with 5% β-mercaptoethanol at 37 °C for 5 minutes and loaded onto a 3% to 8% Tris-acetate gel. The gel is transferred to nitrocellulose and processed for Western blotting by using monoclonal CFTR antibody or polyclonal to GAPDH. Blots are developed by enhanced chemiluminescence. Quantification of the relative amounts of bands C and GAPDH is performed by using NIH ImageJ analysis of scanned films.
Cell Research:[1]
+ Expand
  • Cell lines: FRT (CFTR or F508del-CFTR), HEK-293 (CFTT or F508del-CFTR) , and HBE cells
  • Concentrations: Dissolved in DMSO, final concentrations ~0.1 mM
  • Incubation Time: 24 or 48 hours
  • Method: Cells are exposed to various concentrations of VX-809 for 24 or 48 hours. Ussing chamber techniques are used to record the transepithelial current (IT) resulting from CFTR-mediated chloride transport. The single-channel activity of CFTR is measured by using excised inside-out membrane patch recordings. Immunoblot techniques using themonoclonal CFTR antibody are used to measure CFTR maturation in FRT, HEK-293, or HBE cells expressing CFTR or F508del-CFTR.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 90 mg/mL (198.93 mM)
Ethanol 6 mg/mL (13.26 mM)
Water Insoluble
In vivo Add solvents individually and in order:
30% PEG400+0.5% Tween80+5% propylene glycol
30 mg/mL

* 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 Information

Molecular Weight 452.41
Formula

C24H18F2N2O5

CAS No. 936727-05-8
Storage powder
Synonyms VRT 826809

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02858843 Not yet recruiting Cystic Fibrosis|Diabetes Massachusetts General Hospital August 2016 --
NCT02807415 Recruiting Cystic Fibrosis Hannover Medical School|Heidelberg University|University of Giessen June 2016 --
NCT02797132 Recruiting Cystic Fibrosis Vertex Pharmaceuticals Incorporated May 2016 Phase 3
NCT02653027 Not yet recruiting Diabetes|Cystic Fibrosis Massachusetts General Hospital January 2016 --
NCT02544451 Enrolling by invitation Cystic Fibrosis Vertex Pharmaceuticals Incorporated August 2015 Phase 3
NCT02514473 Completed Cystic Fibrosis Vertex Pharmaceuticals Incorporated July 2015 Phase 3

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID