TY - JOUR T1 - Correction of the ΔPhe508 Cystic Fibrosis Transmembrane Conductance Regulator Trafficking Defect by the Bioavailable Compound Glafenine JF - Molecular Pharmacology JO - Mol Pharmacol SP - 922 LP - 930 DO - 10.1124/mol.109.062679 VL - 77 IS - 6 AU - Renaud Robert AU - Graeme W. Carlile AU - Jie Liao AU - Haouaria Balghi AU - Pierre Lesimple AU - Na Liu AU - Bart Kus AU - Daniela Rotin AU - Martina Wilke AU - Hugo R. de Jonge AU - Bob J. Scholte AU - David Y. Thomas AU - John W. Hanrahan Y1 - 2010/06/01 UR - http://molpharm.aspetjournals.org/content/77/6/922.abstract N2 - Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-activated anion channel expressed in epithelial cells. The most common mutation ΔPhe508 leads to protein misfolding, retention by the endoplasmic reticulum, and degradation. One promising therapeutic approach is to identify drugs that have been developed for other indications but that also correct the CFTR trafficking defect, thereby exploiting their known safety and bioavailability in humans and reducing the time required for clinical development. We have screened approved, marketed, and off-patent drugs with known safety and bioavailability using a ΔPhe508-CFTR trafficking assay. Among the confirmed hits was glafenine, an anthranilic acid derivative with analgesic properties. Its ability to correct the misprocessing of CFTR was confirmed by in vitro and in vivo studies using a concentration that is achieved clinically in plasma (10 μM). Glafenine increased the surface expression of ΔPhe508-CFTR in baby hamster kidney (BHK) cells to ∼40% of that observed for wild-type CFTR, comparable with the known CFTR corrector 4-cyclohexyloxy-2-{1-[4-(4-methoxybenzensulfonyl)-piperazin-1-yl]-ethyl}-quinazoline (VRT-325). Partial correction was confirmed by the appearance of mature CFTR in Western blots and by two assays of halide permeability in unpolarized BHK and human embryonic kidney cells. Incubating polarized CFBE41o− monolayers and intestines isolated from ΔPhe508-CFTR mice (treated ex vivo) with glafenine increased the short-circuit current (Isc) response to forskolin + genistein, and this effect was abolished by 10 μM CFTRinh172. In vivo treatment with glafenine also partially restored total salivary secretion. We conclude that the discovery of glafenine as a CFTR corrector validates the approach of investigating existing drugs for the treatment of CF, although localized delivery or further medicinal chemistry may be needed to reduce side effects.Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics ER -