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Research ArticleArticle

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 and A. S. Verkman
Molecular Pharmacology October 2011, 80 (4) 683-693; DOI: https://doi.org/10.1124/mol.111.073056
Puay-Wah Phuan
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Baoxue Yang
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John M. Knapp
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Alex B. Wood
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Gergely L. Lukacs
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Mark J. Kurth
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A. S. Verkman
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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 single-drug treatment of cystic fibrosis caused by ΔPhe508 mutation.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants DK72517, DK075302, DK86125, DK35124]; the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL73856]; the National Institute of Health National Institute of Biomedical Imaging and Bioengineering [Grant EB00415]; the National Institute of Health National Eye Institute [Grant EY135740]; the Cystic Fibrosis Foundation; the Canadian Cystic Fibrosis Foundation; and a Canada Research Chair (to G.L.L.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.073056.

  • ABBREVIATIONS:

    CF
    cystic fibrosis
    AAT
    arylaminothiazole
    CFTR
    cystic fibrosis transmembrane conductance regulator
    CoPo
    corrector-potentiator
    DCM
    dichloromethane
    ER
    endoplasmic reticulum
    FRT
    Fisher rat thyroid
    YFP
    yellow fluorescence protein
    PBS
    phosphate-buffered saline
    DMSO
    dimethyl sulfoxide
    VX-770
    N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
    VX-809
    3-[6-[[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl]amino]-3-methyl-2-pyridinyl]-benzoic acid
    VRT-532
    pyrazole 4-methyl-2-(5-phenyl-1H-pyrazol-3-yl)-phenol.

  • Received April 16, 2011.
  • Accepted July 5, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (4)
Molecular Pharmacology
Vol. 80, Issue 4
1 Oct 2011
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Research ArticleArticle

Cyanoquinoline ΔPhe508-CFTR Activators

Puay-Wah Phuan, Baoxue Yang, John M. Knapp, Alex B. Wood, Gergely L. Lukacs, Mark J. Kurth and A. S. Verkman
Molecular Pharmacology October 1, 2011, 80 (4) 683-693; DOI: https://doi.org/10.1124/mol.111.073056

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Research ArticleArticle

Cyanoquinoline ΔPhe508-CFTR Activators

Puay-Wah Phuan, Baoxue Yang, John M. Knapp, Alex B. Wood, Gergely L. Lukacs, Mark J. Kurth and A. S. Verkman
Molecular Pharmacology October 1, 2011, 80 (4) 683-693; DOI: https://doi.org/10.1124/mol.111.073056
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