VX-809 (Lumacaftor)通过促进突变型CFTR(F508del-CFTR)的成熟，从而纠正常见于囊性纤维化的CFTR突变，EC50为0.1 μM。VX-809在雌激素受体（ER）水平上起作用的行为，使一部分F508del-CFTR采取正确折叠的方式，退出ER，转移到细胞表面，正常起作用。VX-809作用于表达 F508del-CFTR的Fischer 大鼠甲状腺 (FRT)细胞, VX-809显著提高F508del-CFTR突变，提高7.1 倍，EC50为0.1 μM, 且增强F508del-CFTR调节的氯离子运输，提高5 倍， EC50 为0.5 μM, 而VRT-768作用时具有更高的EC50 值，EC50分别为7.9 μM 和 16 μM。VX-809 (3 μM)作用于表达F508del-CFTR的HEK-293细胞,提高ER中的F508del-CFTR，提高6倍。

＞98%

Store at -20℃ for one year（Powder）；Store at 2-4℃ for two weeks；Store at -20℃ for six months after dissolution.

鲁玛卡托；Lumacaftor；VRT 826809

White to off white powder

DMSO : 50 mg/mL (110.52 mM; Need ultrasonic)

CFTR

In fischer rat thyroid (FRT) cells, VX-809 improves F508del-CFTR maturation by 7.1±0.3 fold (n=3) compared with vehicle-treated cells (EC50, 0.1±0.1 μM; n=3) and enhances F508del-CFTR-mediated chloride transport by approximately fivefold (EC50, 0.5±0.1 μM; n=3). At VX-809 concentrations greater than 10 μM, the response is reduced, resulting in a bell-shaped dose-response relationship with an IC50 of approximately 100 μM. VX-809 is orally bioavailable in rats and achieved in vivo plasma levels significantly above concentrations required for in vitro efficacy. VX-809 produces a concentration-dependent increase in the HRP luminescence signal after incubation with cells at 37°C or 27°C in both cell lines, with a similar EC50 value of approximately 0.3 µM. In F508-HRP CFBE41o- cells at 37°C, VX-809 increases the signal maximally to approximately 250 luminescence arbitrary units (a.u.) over the DMSO control baseline of approximately 60 a.u., representing an approximately 4-fold signal increase. Similarly, with the R1070W-HRP CFBE41o- cells, VX-809 increases the signal maximally to approximately 220 a.u. over the DMSO control baseline of approximately 85 a.u., representing an approximately 2.5-fold signal increase. Therefore, both cell lines produced robust signals with a good dynamic range for high-throughput screening.

Oral dosing of 1 mg/kg VX-809 in male Sprague-Dawley rats results in a Cmax of 2.4±1.3 μM with a t1/2 of 7.7±0.4 h (mean±SD; n=3), indicating that that VX-809 is orally bioavailable and able to reach plasma levels that significantly exceeded EC50s for F508del-CFTR correction.