Lumacaftor (VX-809)

製品コードS1565 バッチS156502

化学情報

	Synonyms	VRT 826809	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₂₄H₁₈F₂N₂O₅
	分子量	452.41	CAS No.	936727-05-8
Solubility (25°C)*	体外	DMSO	90 mg/mL (198.93 mM)
		Ethanol	6 mg/mL (13.26 mM)
		Water	Insoluble
* <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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	Lumacaftor (VX-809, VRT 826809) 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.
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]
in vivo	Lumacaftor (VX-809; VRT 826809) is a CFTR modulator that corrects the folding and trafficking of CFTR protein.
特徴	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	F508del-CFTR maturation
キナーゼアッセイ	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	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 (I_T) 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.
動物実験	動物モデル	Male Sprague– Dawley rats
	投薬量	1 mg/kg
	投与方法	p.o.

参考

[1] Van Goor F, et al. Proc Natl Acad Sci U S A, 2011, 108(46), 18843-18848.

カスタマーフィードバック

: Data from [J Biol Chem, 2012, 287, 43630-8]

: , , Xuehong Liu of Oregon Health & Science University

: ,

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

The Inhibition of the Membrane-Bound Transcription Factor Site-1 Protease (MBTP1) Alleviates the p.Phe508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Defects in Cystic Fibrosis Cells [ Cells, 2024, 13(2)185]	PubMed: 38247876
Comprehensive Assessment of CFTR Modulators' Therapeutic Efficiency for N1303K Variant [ Int J Mol Sci, 2024, 25(5)2770]	PubMed: 38474016
PTI-801 (posenacaftor) shares a common mechanism with VX-445 (elexacaftor) to rescue p.Phe508del-CFTR [ Eur J Pharmacol, 2024, 967:176390]	PubMed: 38336013
CFTR modulators response of S737F and T465N CFTR variants on patient-derived rectal organoids [ Orphanet J Rare Dis, 2024, 19(1):343]	PubMed: 39272186
Activity and inhibition of the SARS-CoV-2 Omicron nsp13 R392C variant using RNA duplex unwinding assays [ SLAS Discov, 2024, S2472-5552(24)00007-8]	PubMed: 38301954
Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models [ Nat Commun, 2023, 10.1038/s41467-023-42948-2]	PubMed: 37951948
ABC-transporter CFTR folds with high fidelity through a modular, stepwise pathway [ Cell Mol Life Sci, 2023, 80(1):33]	PubMed: 36609925
SARS-CoV-2-Mediated Lung Edema and Replication Are Diminished by Cystic Fibrosis Transmembrane Conductance Regulator Modulators [ mBio, 2023, e0313622.]	PubMed: 36625656
Easy-to-Build and Reusable Microfluidic Device for the Dynamic Culture of Human Bronchial Cystic Fibrosis Epithelia [ ACS Biomater Sci Eng, 2023, 9(5):2780-2792]	PubMed: 37019688
In silico analysis and theratyping of an ultra-rare CFTR genotype (W57G/A234D) in primary human rectal and nasal epithelial cells [ iScience, 2023, 26(11):108180]	PubMed: 38026150

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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