Cyanoquinolines with independent corrector and potentiator activities restore ΔPhe508-cystic fibrosis transmembrane conductance regulator chloride channel function in cystic fibrosis

Puay Wah Phuan, Baoxue Yang, John M. Knapp, Alex B. Wood, Gergely L. Lukacs, Mark J. Kurth, Alan S. Verkman

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

The ΔPhe508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein impairs its folding, stability, and chloride channel gating. Although small molecules that separately correct defective ΔPhe508-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 small molecules not tested previously 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. N-(2-((3-Cyano-5,7-dimethylquinolin-2- yl)amino)ethyl)-3-methoxybenzamide (CoPo-22), which was synthesized in six steps in 52% overall yield, had low micromolar EC50 for ΔPhe508-CFTR corrector and potentiator activities by short-circuit current assay. Maximal corrector and potentiator activities were comparable with 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 singledrug treatment of cystic fibrosis caused by ΔPhe508 mutation.

Original languageEnglish (US)
Pages (from-to)683-693
Number of pages11
JournalMolecular Pharmacology
Volume80
Issue number4
DOIs
StatePublished - Oct 2011

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Fingerprint Dive into the research topics of 'Cyanoquinolines with independent corrector and potentiator activities restore ΔPhe508-cystic fibrosis transmembrane conductance regulator chloride channel function in cystic fibrosis'. Together they form a unique fingerprint.

  • Cite this