生物活性

• 靶点	CFTR (F508del) EC50:0.1μM

• 描述Cystic fibrosis (CF) is a genetic disorder with the loss of chloride transport due to the defects in CF transmembrane conductance regulator (CFTR) protein. VX-809 is a CFTP corrector that partially increases the delivery of CFTR to cell surface, thereby restoring the function of chloride transportation. It improved the maturation of F508del-CFTR, the most common CFTR mutation, in FRT cells with an EC50 value at 0.1 μM; and increased F508del-CFTR-mediated chloride transport with an EC50 at 0.5 μM. Data from F508del-HEK293 cells showed that incubation with 3 μM VX-809 for 24 hours increased F508del-CFTR exit from the endoplasmic reticulum by 6 folds compared with control cells. Also, cultured F508del-HBE cells treated with 3 μM VX-809 for 48 hours showed 14% higher maximal level of chloride transport compared to normal HBE cells^[5]. In a human lung epithelium-derived cell line that was transfected with horseradish peroxidase (HRP)-tagged CFTR (F508-HRP CFBE41o^-), cells treated with 2 μM VX-809 at 37C for 24 hours showed 4-fold HRP luminescence signal increase compared to DMSO-treated cells. Similar result was also found in R1070W-HRP CFBE41o^- cells with 2.5-fold signal increase after VX-809 treatment at the concentration of 2 μM^[6]. A phase 2 study in homozygous CF patients reported that daily intake of 100 and 200 mg VX-809 for 28 days significantly decreased their elevated sweat chloride values^[7].
• 作用机制VX-809 suppresses the folding defects of transmembrane conductance regulator (CFTR) protein by stabilizing an N-terminal domain in the CFTR that contains membrane-spanning domain 1^[8].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human CFBE41o cells	-	Function 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

• 动物研究
  剂量	Mice: 1.5 mg/kg[3] (i.v.) Rat: 1 mg/kg[4] (p.o.)， 1 mg/kg - 600 mg/kg[3] (p.o.), 1 mg/kg - 5 mg/kg[3] (i.v.)
  给药途径	i.v., p.o.
  动物药代数据	Animal Rats[3] Dose 30 mg/kg (p.o.) 3 mg/kg (i.v.) Administration p.o. i.v. F 69.7% (p.o.) T1/2 6.46 h (p.o.) 8.62 h (i.v.) Tmax 2.0 h (p.o.) 0.083 h (i.v.) Cmax 66200 ng/g (p.o.) 24600 ng/g (i.v.) AUC0→∞ 410000 ng·h/g (p.o.) 58900 ng·h/g (i.v.) AUC0→t 410000 ng·h/g (p.o.) 58900 ng·h/g (i.v.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03474042	Cystic Fibrosis	Phase 2	Completed	-	Germany ... more >> Study Site II Berlin, Germany Study Site X Dresden, Germany Study Site III Essen, Germany Study Site IV Frankfurt, Germany Study Site I Heidelberg, Germany Study Site V Köln, Germany Study Site VI München, Germany Study Site IX Stuttgart, Germany Study Site VIII Tübingen, Germany Collapse <<
  NCT02821130	-	-	Active, not recruiting	December 2019	Canada, British Columbia ... more >> UBC James Hogg Research Centre, St. Paul's Hospital Vancouver, British Columbia, Canada, V6Z1Y6 Collapse <<
  NCT02965326	Cystic Fibrosis	Not Applicable	Recruiting	October 2020	France ... more >> Necker Hospital Recruiting Paris, France, 75014 Contact: SERMET Isabelle, Professor    01 44 49 48 87    isabelle.sermet@nck.aphp.fr    Principal Investigator: SERMET Isabelle, Professor Collapse <<

• 更多