PT - JOURNAL ARTICLE AU - Puay-Wah Phuan AU - Baoxue Yang AU - John Knapp AU - Alex Wood AU - Gergely L Lukacs AU - Mark J Kurth AU - A S Verkman TI - Cyanoquinolines with Independent Corrector and Potentiator Activities Restore ∆F508-CFTR Chloride Channel Function in Cystic Fibrosis AID - 10.1124/mol.111.073056 DP - 2011 Jul 05 TA - Molecular Pharmacology PG - mol.111.073056 4099 - http://molpharm.aspetjournals.org/content/early/2011/07/05/mol.111.073056.short 4100 - http://molpharm.aspetjournals.org/content/early/2011/07/05/mol.111.073056.full AB - The ∆F508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein impairs its folding, stability and chloride channel gating. Though small molecules that separately correct defective ∆F508-CFTR folding/cellular processing ('correctors') or chloride channel gating ('potentiators') have been discovered and are in clinical trials, single compounds with bona fide dual corrector and potentiator activities have not been identified. Here, screening of ~110,000 not-previously tested small molecules revealed a cyanoquinoline class of compounds with independent corrector and potentiator activities (termed CoPo). Analysis of 180 CoPo analogs revealed 6 compounds with dual corrector and potentiator activities, and 13 compounds with only potentiator activity. CoPo-22, which was synthesized in 6 steps in 52 % overall yield, had low micromolar EC50 for ∆F508-CFTR corrector and potentiator activities by short-circuit current assay. Maximal corrector and potentiator activities were comparable to those conferred by the bithiazole Corr-4a and the flavone genistein, respectively. CoPo-22 also activated wild type and G551D CFTR chloride conductance within minutes, in a forskolin-dependent manner. Compounds with dual corrector and potentiator activities may be useful for single drug therapy of CF caused by ∆F508 mutation.