ArticleMolecular pharmacology2011
Cyanoquinolines with independent corrector and potentiator activities restore ΔPhe508-cystic fibrosis transmembrane conductance regulator chloride channel function in cystic fibrosis.
Article in Molecular pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 60 citations in OpenAlex.
- CFTR Modulators: From Mechanism to Targeted Therapeutics.Handbook of experimental pharmacology · 2024Article
- Overview of CFTR activators and their recent studies for dry eye disease: a review.RSC medicinal chemistry · 2023Review
- State of the Art on Approved Cystic Fibrosis Transmembrane Conductance Regulator (Pharmaceuticals (Basel, Switzerland) · 2021Review
- Comprehensive Analysis of Chemical Structures That Have Been Tested as CFTR Activating Substances in a Publicly Available Database CandActCFTR.Frontiers in pharmacology · 2021Article
- New Insights into the Binding Features of F508del CFTR Potentiators: A Molecular Docking, Pharmacophore Mapping and QSAR Analysis Approach.Pharmaceuticals (Basel, Switzerland) · 2020Article
- Recent Strategic Advances in CFTR Drug Discovery: An Overview.International journal of molecular sciences · 2020Review
- Innovative Therapies for Cystic Fibrosis: The Road from Treatment to Cure.Molecular diagnosis & therapy · 2019Review
- Molecular basis of cystic fibrosis: from bench to bedside.Annals of translational medicine · 2018Review
- ΔF508-CFTR Modulator Screen Based on Cell Surface Targeting of a Chimeric Nucleotide Binding Domain 1 Reporter.SLAS discovery : advancing life sciences R & D · 2018Article
- Personalized medicine in CF: from modulator development to therapy for cystic fibrosis patients with rare CFTR mutations.American journal of physiology. Lung cellular and molecular physiology · 2018Review
- Partial rescue of F508del-cystic fibrosis transmembrane conductance regulator channel gating with modest improvement of protein processing, but not stability, by a dual-acting small molecule.British journal of pharmacology · 2018Article
- Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators.Frontiers in pharmacology · 2018Article
- High-Potency Phenylquinoxalinone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activators.Journal of medicinal chemistry · 2017Article
- Potentiators exert distinct effects on human, murine, and Xenopus CFTR.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- Lumacaftor/ivacaftor combination for cystic fibrosis patients homozygous for Phe508del-CFTR.Drugs of today (Barcelona, Spain : 1998) · 2016Review
- Finding new drugs to enhance anion secretion in cystic fibrosis: Toward suitable systems for better drug screening. Report on the pre-conference meeting to the 12th ECFS Basic Science Conference, Albufeira, 25-28 March 2015.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2015Article
- PharmGKB summary: very important pharmacogene information for CFTR.Pharmacogenetics and genomics · 2015Article
- Rescuing ΔF508 CFTR with trimethylangelicin, a dual-acting corrector and potentiator.American journal of physiology. Lung cellular and molecular physiology · 2014Review
- A genomic signature approach to rescue ΔF508-cystic fibrosis transmembrane conductance regulator biosynthesis and function.American journal of respiratory cell and molecular biology · 2014Article
- Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis.Science translational medicine · 2014Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
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 EC(50) 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.
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Registered trials
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