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.
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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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