VX-809 (Lumacaftor) 化学構造
分子量: 452.41

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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 VX-809 (Lumacaftor)は、0.1μMのEC50による嚢胞性線維症膜内外コンダクタンス監査機関(CFTR)モジュレータです。
ターゲット CFTR
IC50 0.1 μM [1]
In vitro試験 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]
In vivo試験
臨床試験 A Phase II study of VX-809 in cystic fibrosis subjects with the ΔF508-CFTR gene mutation has been completed. A Phase II study of VX-809 alone and in combination with VX-770 in cystic fibrosis (CF) patients with the F508del-CFTR mutation is ongoing.
特集 Higher specificity and efficacy relative to other CFTR defect drugs.

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

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.

細胞アッセイ: [1]

細胞株 FRT (CFTR or F508del-CFTR), HEK-293 (CFTT or F508del-CFTR) , and HBE cells
濃度 Dissolved in DMSO, final concentrations ~0.1 mM
反応時間 24 or 48 hours
実験の流れ 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.

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 VX-809 (Lumacaftor) SDF
分子量 452.41
化学式

C24H18F2N2O5

CAS No. 936727-05-8
保管 2年-20℃
6月-80℃in solvent
別名 VRT 826809
溶解度 (25°C) * In vitro DMSO 90 mg/mL (198.93 mM)
エタノール 6 mg/mL (13.26 mM)
<1 mg/mL (<1 mM)
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 30 mg/mL
* <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 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

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Rating
Source J Biol Chem, 2012, 287, 43630-8. VX-809 (Lumacaftor) purchased from Selleck
Method Rescue of △F508-CFTR Processing
Cell Lines HeLa cell lines
Concentrations 3 μM
Incubation Time 24 h
Results SPT trajectories of △F508CFTR diffusion following VX-809 correction appeared less confined than those of wtCFTR under control conditions (Fig. A, red and black trajectories) and range values differed significantly (Fig. B, bars 1 and 3). Expression of mCh-CFTR-C increased thediffusion of VX-809-corrected △F508CFTR (Fig. A, blue )to that found for wtCFTR with mCh-CFTR-C or for CFTR△PDZ (Fig. B, bars 4–6 ), confirming the involvement of PDZ interactions in restricting r△F508CFTR mobility after VX-809 treatment. VX-809 treat-ment did not alter the diffusion of wtCFTR or CFTRPDZ, suggesting that VX-809 does not perturb plasma membrane properties.

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Rating
Source Xuehong Liu of Oregon Health & Science University. VX-809 (Lumacaftor) purchased from Selleck
Method Two-electrode-voltage clamp
Cell Lines oocytes
Concentrations 5 μM
Incubation Time 3 d
Results VX809 inceases the expression of DF508 CFTR in oocytes.

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Rating
Source VX-809 (Lumacaftor) purchased from Selleck
Method Short-Circuit Recordings
Cell Lines CF-HBE cells
Concentrations 10 μM
Incubation Time 24 h
Results As demonstrated in Figure A&B, both VX-809 and CF-106951 partially rescued the△F508-CFTR mediatedIsc in CF-HBE cells at 24 h. TGF- β1 inhibited the △ F508-CFTR mediated Isc rescued by either VX-809 or CF-106951 (Fig. C–F).

文献中の引用 (14)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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