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Lumacaftor (VX-809)
別名: VRT 826809
Lumacaftor (VX-809, VRT 826809)通過促進突變型CFTR(F508del-CFTR)的成熟，從而糾正囊性纖維癥中常見的CFTR突變，在fisher大鼠甲狀腺細胞中EC50為0.1 μM。Phase 3。
Lumacaftor (VX-809) Chemical Structure
CAS: 936727-05-8
產(chǎn)品質(zhì)控
批次：
純度：
99.96%
99.96
Lumacaftor (VX-809)相關(guān)產(chǎn)品
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| 相關(guān)化合物庫 | FDA藥物庫 天然產(chǎn)物庫 離子通道配體庫 外泌體分泌相關(guān)化合物庫 鈣通道阻滯劑庫 | 點擊展開 |
相關(guān)信號通路圖
細胞實驗數(shù)據(jù)示例
| 細胞系 | 實驗類型 | 給藥濃度 | 孵育時間 | 活性描述 | 文獻信息 |
|---|---|---|---|---|---|
| CFBE41o | Corrector assay | 1 uM | 24 hrs | Corrector activity at CFTR F508-del mutant (unknown origin) expressed in human CFBE41o cells harboring HS-YFP assessed as increase in matured protein levels at cell surface at 1 uM after 24 hrs by electrophoretic mobility assay | 29272749 |
| CFBE41o | Corrector assay | 1 uM | 24 hrs | Corrector activity at CFTR F508del mutant (unknown origin) expressed in human CFBE41o cells assessed as increase in size of cAMP-dependent current at 1 uM after 24 hrs measured at +100 mV by whole cell patch clamp assay | 26041577 |
| CFBE41o | Corrector assay | 24 hrs | Corrector activity at CFTR F508-del mutant (unknown origin) expressed in human CFBE41o cells harboring HS-YFP preincubated for 24 hrs followed by forskolin/genistein stimulation for 30 mins by fluorescence assay, EC50 = 2.5704 μM. | 29272749 | |
| FRT | Corrector assay | 25 mins | Corrector activity at human CFTR F508 deletion mutant expressed in FRT cells incubated for 25 mins with forskolin by YFP-based fluorescence analysis relative to control, EC50 = 2.6 μM. | 26561003 | |
| TC32 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells | 29435139 | ||
| U-2 OS | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells | 29435139 | ||
| A673 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells | 29435139 | ||
| DAOY | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells | 29435139 | ||
| Saos-2 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells | 29435139 | ||
| BT-37 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells | 29435139 | ||
| RD | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells | 29435139 | ||
| SK-N-SH | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells | 29435139 | ||
| BT-12 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells | 29435139 | ||
| MG 63 (6-TG R) | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells | 29435139 | ||
| NB1643 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells | 29435139 | ||
| BT-12 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-12 cells | 29435139 | ||
| OHS-50 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells | 29435139 | ||
| fibroblast cells | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for control Hh wild type fibroblast cells | 29435139 | ||
| Rh41 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells | 29435139 | ||
| Rh30 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh30 cells | 29435139 | ||
| U-2 OS | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for U-2 OS cells | 29435139 | ||
| Rh41 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh41 cells | 29435139 | ||
| RD | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for RD cells | 29435139 | ||
| SJ-GBM2 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells | 29435139 | ||
| SK-N-MC | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells | 29435139 | ||
| NB-EBc1 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells | 29435139 | ||
| LAN-5 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells | 29435139 | ||
| Rh18 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells | 29435139 | ||
| HBE | Corrector assay | Corrector activity at CFTR F508del/F508del mutant in primary HBE cells assessed as increase in chloride ion current across apical membrane measured 18 to 24 hrs post compound treatment on basolateral side of cells in presence of channel potentiator GLPG18 | 29251932 | ||
| CFBE41o | Corrector assay | Corrector activity at CFTR F508del mutant (unknown origin) expressed in human CFBE41o cells assessed as increase in fully glycosylated protein by western blot analysis | 26041577 | ||
| 點擊查看更多細胞系數(shù)據(jù) | |||||
生物活性
| 產(chǎn)品描述 | Lumacaftor (VX-809, VRT 826809)通過促進突變型CFTR(F508del-CFTR)的成熟，從而糾正囊性纖維癥中常見的CFTR突變，在fisher大鼠甲狀腺細胞中EC50為0.1 μM。Phase 3。 | ||
|---|---|---|---|
| 特性 | 在糾正CFTR缺陷方面，VX-809比之前報道的藥物特異性更強，且更有效。 | ||
| 靶點 |
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| 體外研究(In Vitro) | ||||
| 體外研究活性 | VX-809在雌激素受體（ER）水平上起作用的行為，使一部分F508del-CFTR采取正確折疊的方式，退出ER，轉(zhuǎn)移到細胞表面，正常起作用。VX-809作用于表達 F508del-CFTR的Fischer 大鼠甲狀腺 (FRT)細胞, VX-809顯著提高F508del-CFTR突變，提高7.1 倍，EC50為0.1 μM, 且增強F508del-CFTR調(diào)節(jié)的氯離子運輸，提高5 倍， EC50 為0.5 μM, 而VRT-768作用時具有更高的EC50 值，EC50分別為7.9 μM 和 16 μM。VX-809 (3 μM)作用于表達F508del-CFTR的HEK-293細胞,提高ER中的F508del-CFTR，提高6倍。VX-809作用于攜帶F508del-CFTR突變的原代人支氣管上皮 (HBE)細胞，提高CFTR成熟度，且增強氯離子分泌，EC50分別為350 nM和81 nM,比Corr-4a和VRT-325更有效。VX-809修正的F508del-CFTR具有單通道開發(fā)概率，為0.39，與正常CFTR 類似，正常CFTR為0.40。與VX-770不同, VX-809不是CFTR增強劑，急劇加入VX-809不會對F508del-CFTR 功能造成影響。與VRT-325和Corr-4a相反, VX-809 不會促進正常或突變形式hERG 或P-gp的進程,及其他疾病引起錯誤定位的蛋白質(zhì)，包括α1-抗胰蛋白酶Z突變 (E342K-α1-AT)或N370S-β-葡萄糖苷酶, 說明VX-809特異性作用于CFTR。 |
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|---|---|---|---|---|
| 激酶實驗 | F508del-CFTR成熟度 | |||
| 用濃度不斷增高的VX-809處理穩(wěn)定表達F508del-CFTR的Fischer大鼠甲狀腺(FRT)細胞48小時。溫育后，細胞收集在冰凍D-PBS溶液中 (沒有鈣和鎂)，然后按1,000 × g 轉(zhuǎn)速在4oC下離心。細胞顆粒溶解1% Nonidet P-40, 0.5%去氧膽酸鈉，200 mM NaCl, 10 mM Tris, pH 7.8, 及 1 mM EDTA和蛋白酶抑制劑混合物中(1:250)，然后在冰上放置30分鐘。裂解物在10,000×g轉(zhuǎn)速4oC下旋轉(zhuǎn)10分鐘，將細胞核和不溶性物質(zhì)制成顆粒狀。12 μg 全部蛋白在Laemmli buffer 中與5% β-巰基乙醇在37oC加熱5分鐘，然后上樣到3% 到8% Tris-乙酸凝膠上。凝膠轉(zhuǎn)移到硝化纖維素中，使用單克隆CFTR抗體或 GAPDH多克隆抗體進行 Western blotting。通過增強發(fā)光而進行印跡。通過掃描片的 NIH ImageJ 分析而而測量C帶和GAPDH的相對量。 | ||||
| 細胞實驗 | 細胞系 | FRT(CFTR 或 F508del-CFTR), HEK-293 (CFTT 或 F508del-CFTR), 和HBE | ||
| 濃度 | 溶于DMSO, 終濃度為~0.1 mM | |||
| 孵育時間 | 24 或 48 小時 | |||
| 方法 | 使用濃度不斷增高的VX-809處理細胞24或48小時。使用Ussing chamber技術(shù)記錄 CFTR介導(dǎo)氯離子運輸中的跨膜電流 (IT)結(jié)果。通過使用離體的內(nèi)面外向式膜片鉗測量CFTR單通道活性。使用單克隆CFTR 抗體及免疫印跡技術(shù)測量表達CFTR或F508del-CFTR的FRT, HEK-293, 或 HBE細胞中CFTR成熟度。 |
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| 實驗圖片 | 檢測方法 | 檢測指標(biāo) | 實驗圖片 | PMID |
| Immunofluorescence | CFTR / USP13 Cell surface kAE1 / kAE1 |
|
30618756 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT03512119 | Completed | Cystic Fibrosis Homozygous for Phe 508 Del CFTR|Glucose Intolerance or Newly Diagnosis Diabetes |
University Hospital Strasbourg France |
February 11 2016 | -- |
| NCT02589236 | Completed | Cystic Fibrosis |
Nivalis Therapeutics Inc.|Medidata Solutions |
November 2015 | Phase 2 |
| NCT02514473 | Completed | Cystic Fibrosis |
Vertex Pharmaceuticals Incorporated |
July 2015 | Phase 3 |
| NCT01899105 | Completed | Cystic Fibrosis |
Vertex Pharmaceuticals Incorporated |
July 2013 | Phase 1 |
化學(xué)信息&溶解度
| 分子量 | 452.41 | 分子式 | C24H18F2N2O5 |
| CAS號 | 936727-05-8 | SDF | Download Lumacaftor (VX-809) SDF |
| Smiles | CC1=C(N=C(C=C1)NC(=O)C2(CC2)C3=CC4=C(C=C3)OC(O4)(F)F)C5=CC(=CC=C5)C(=O)O | ||
| 儲存條件(自收到貨起) | |||
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體外溶解度 |
DMSO : 90 mg/mL ( (198.93 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO) Ethanol : 6 mg/mL (13.26 mM) Water : Insoluble |
摩爾濃度計算器 |
|
體內(nèi)溶解度 現(xiàn)配現(xiàn)用，請按從左到右的順序依次添加，澄清后再加入下一溶劑 |
動物體內(nèi)配方計算器 | ||||
實驗計算
動物體內(nèi)配方計算器（澄清溶液）
第一步：請輸入基本實驗信息（考慮到實驗過程中的損耗，建議多配一只動物的藥量）
mg/kg
g
μL
只
第二步：請輸入動物體內(nèi)配方組成（配方適用于不溶于水的藥物；不同批次藥物配方比例不同，請聯(lián)系Selleck為您提供正確的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
計算結(jié)果：
工作液濃度： mg/ml；
DMSO母液配制方法： mg 藥物溶于μL DMSO溶液（母液濃度mg/mL，注：如該濃度超過該批次藥物DMSO溶解度，請先聯(lián)系Selleck）；
體內(nèi)配方配制方法：取μL DMSO母液，加入μL PEG300，混勻澄清后加入μL Tween 80，混勻澄清后加入μL ddH2O，混勻澄清。
體內(nèi)配方配制方法：取μL DMSO母液，加入μL Corn oil，混勻澄清。
注意：1. 首先保證母液是澄清的；
2.一定要按照順序依次將溶劑加入，進行下一步操作之前必須保證上一步操作得到的是澄清的溶液，可采用渦旋、超聲或水浴加熱等物理方法助溶。
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