ArticleJournal of cystic fibrosis : official journal of the European Cystic Fibrosis Society2018
Combination potentiator ('co-potentiator') therapy for CF caused by CFTR mutants, including N1303K, that are poorly responsive to single potentiators.
Article in Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 64 citations in OpenAlex.
- Triple potentiator combinations increase the functional correction of several CFTR gating mutants.npj drug discovery · 2026Article
- Inhibition of the QPCT-PDIA4 axis rescues ΔF508 and N1303K CFTR in cystic fibrosis.Nature communications · 2026Article
- Chronic and acute modulator treatment restore wild-type-like activity and stability to the primary cystic fibrosis-causingProceedings of the National Academy of Sciences of the United States of America · 2026Article
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- Recent developments in cystic fibrosis drug discovery: where are we today?Expert opinion on drug discovery · 2025Review
- Unraveling the Mechanism of Action, Binding Sites, and Therapeutic Advances of CFTR Modulators: A Narrative Review.Current issues in molecular biology · 2025Review
- Rescue of Mutant CFTR Channel Activity by Investigational Co-Potentiator Therapy.Biomedicines · 2025Article
- Beyond Trikafta: new models to assess tissue dependent rescue of N1303K-CFTR.Frontiers in pharmacology · 2025Article
- ATP-Binding Cassette and Solute Carrier Transporters: Understanding Their Mechanisms and Drug Modulation Through Structural and Modeling Approaches.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Systematic deletion of symmetricalNAR molecular medicine · 2024Article
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- Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor.Molecules (Basel, Switzerland) · 2024Review
- Two rare variants that affect the same amino acid in CFTR have distinct responses to ivacaftor.The Journal of physiology · 2024Article
- A Novel 7ACS medicinal chemistry letters · 2023Article
- Additive Potentiation of R334W-CFTR Function by Novel Small Molecules.Journal of personalized medicine · 2023Article
- Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy.Bioscience reports · 2022Review
- One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies.Cells · 2022Review
- A small molecule CFTR potentiator restores ATP-dependent channel gating to the cystic fibrosis mutant G551D-CFTR.British journal of pharmacology · 2022Article
- Novel CFTR modulator combinations maximise rescue of G85E and N1303K in rectal organoids.ERJ open research · 2022Article
- Molecular dynamics and functional characterization of I37R-CFTR lasso mutation provide insights into channel gating activity.iScience · 2022Article
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundCurrent modulator therapies for some cystic fibrosis-causing CFTR mutants, including N1303K, have limited efficacy. We provide evidence here to support combination potentiator (co-potentiator) therapy for mutant CFTRs that are poorly responsive to single potentiators.
methodsFunctional synergy screens done on N1303K and W1282X CFTR, in which small molecules were tested with VX-770, identified arylsulfonamide-pyrrolopyridine, phenoxy-benzimidazole and flavone co-potentiators.
resultsA previously identified arylsulfonamide-pyrrolopyridine co-potentiator (ASP-11) added with VX-770 increased N1303K-CFTR current 7-fold more than VX-770 alone. ASP-11 increased by ~65% of the current of G551D-CFTR compared to VX-770, was additive with VX-770 on F508del-CFTR, and activated wild-type CFTR in the absence of a cAMP agonist. ASP-11 efficacy with VX-770 was demonstrated in primary CF human airway cell cultures having N1303K, W1282X and G551D CFTR mutations. Structure-activity studies on 11 synthesized ASP-11 analogs produced compounds with EC
conclusionsThese studies support combination potentiator therapy for CF caused by some CFTR mutations that are not effectively treated by single potentiators.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.