PT - JOURNAL ARTICLE AU - Puay-Wah Phuan AU - Guido Veit AU - Joseph Tan AU - Walter E Finkbeiner AU - Gergely L Lukacs AU - Alan S Verkman TI - Potentiators of Defective ΔF508-CFTR Channel Gating that do not Interfere with Corrector Action AID - 10.1124/mol.115.099689 DP - 2015 Jan 01 TA - Molecular Pharmacology PG - mol.115.099689 4099 - http://molpharm.aspetjournals.org/content/early/2015/08/05/mol.115.099689.short 4100 - http://molpharm.aspetjournals.org/content/early/2015/08/05/mol.115.099689.full AB - Combination drug therapies under development for cystic fibrosis (CF) caused by the ΔF508 mutation in 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 VX-770 (Ivacaftor) reduces ΔF508-CFTR cellular stability and the efficacy of investigational correctors, including VX-809 and VX-661, 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 ΔF508-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 EC50 for ΔF508-CFTR potentiation down to 18 nM, and do not reduce corrector efficacy in heterologous ΔF508-CFTR expressing cells or in primary cultures of ΔF508/∆F508 human bronchial epithelia. The ΔF508-CFTR potentiators also activated wildtype and G551D-CFTR, albeit weakly. The efficacy of combination therapy for CF caused by the ΔF508 mutation may be improved by replacement of VX-770 with a potentiator that does not interfere with corrector action.