title: Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809.
abstract: Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC(50), 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.
authors: Vertex Pharmaceuticals, San Diego, CA 92121, USA.
authors: Fredrick
authors: F
authors: Van Goor
authors: Sabine
authors: S
authors: Hadida
authors: Peter D J
authors: PD
authors: Grootenhuis
authors: Bill
authors: B
authors: Burton
authors: Jeffrey H
authors: JH
authors: Stack
authors: Kimberly S
authors: KS
authors: Straley
authors: Caroline J
authors: CJ
authors: Decker
authors: Mark
authors: M
authors: Miller
authors: Jason
authors: J
authors: McCartney
authors: Eric R
authors: ER
authors: Olson
authors: Jeffrey J
authors: JJ
authors: Wine
authors: Ray A
authors: RA
authors: Frizzell
authors: Melissa
authors: M
authors: Ashlock
authors: Paul A
authors: PA
authors: Negulescu
mesh_terms: D000631:Aminopyridines / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000627:therapeutic use*; D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002712:Chlorides / Q000737:chemistry; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000166:cytology; D006720:Homozygote; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000473:pathology; D008957:Models, Genetic; D009154:Mutation
chemical_list: D000631:Aminopyridines; D052117:Benzodioxoles; C505032:CFTR protein, human; D002712:Chlorides; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C569105:lumacaftor