PT  - JOURNAL ARTICLE
AU  - Puay-Wah Phuan
AU  - Guido Veit
AU  - Joseph A. Tan
AU  - Walter E. Finkbeiner
AU  - Gergely L. Lukacs
AU  - A. S. Verkman
TI  - Potentiators of Defective ΔF508–CFTR Gating that Do Not Interfere with Corrector Action
AID  - 10.1124/mol.115.099689
DP  - 2015 Oct 01
TA  - Molecular Pharmacology
PG  - 791--799
VI  - 88
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/88/4/791.short
4100  - http://molpharm.aspetjournals.org/content/88/4/791.full
SO  - Mol Pharmacol2015 Oct 01; 88
AB  - Combination drug therapies under development for cystic fibrosis caused by the ∆F508 mutation in cystic fibrosis transmembrane conductance regulator (CFTR) include a “corrector” to improve its cellular processing and a “potentiator” to improve its chloride channel function. Recently, it was reported that the approved potentiator N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Ivacaftor) reduces ∆F508-CFTR cellular stability and the efficacy of investigational correctors, including 3-(6-[([1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl) amino]-3-methyl-2-pyridinyl)-benzoic acid and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl), which might contribute to the modest reported efficacy of combination therapy in clinical trials. Here, we report the identification and characterization of potentiators that do not interfere with ∆F508-CFTR stability or corrector action. High-throughput screening and structure-activity analysis identified several classes of potentiators that do not impair corrector action, including tetrahydrobenzothiophenes, thiooxoaminothiazoles, and pyrazole-pyrrole-isoxazoles. The most potent compounds have an EC50 for ∆F508-CFTR potentiation down to 18 nM and do not reduce corrector efficacy in heterologous ∆F508-CFTR–expressing cells or primary cultures of ∆F508/∆F508 human bronchial epithelia. The ΔF508-CFTR potentiators also activated wild-type and G551D CFTR, albeit weakly. The efficacy of combination therapy for cystic fibrosis caused by the ∆F508 mutation may be improved by replacement of Ivacaftor with a potentiator that does not interfere with corrector action.