ArticleMolecular pharmacology2013
Novel amino-carbonitrile-pyrazole identified in a small molecule screen activates wild-type and ΔF508 cystic fibrosis transmembrane conductance regulator in the absence of a cAMP agonist.
Article in Molecular pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 22 citations in OpenAlex.
- Barriers to the Pharmacologic Rescue of W1282X CFTR.Biochemistry · 2026Article
- Beyond the mutations: spatiotemporal regulation of CFTR by cAMP and calcium signaling in epithelial physiology and cystic fibrosis.Cellular & molecular biology letters · 2025Review
- VX-770, CInternational journal of molecular sciences · 2025Article
- Overview of CFTR activators and their recent studies for dry eye disease: a review.RSC medicinal chemistry · 2023Review
- Receptor-mediated activation of CFTR via prostaglandin signaling pathways in the airway.American journal of physiology. Lung cellular and molecular physiology · 2022Article
- Comprehensive Analysis of Chemical Structures That Have Been Tested as CFTR Activating Substances in a Publicly Available Database CandActCFTR.Frontiers in pharmacology · 2021Article
- Effect of apical chloride concentration on the measurement of responses to CFTR modulation in airway epithelia cultured from nasal brushings.Physiological reports · 2020Article
- Reducing Limitation in Probe Design: The Development of a Diazirine-Compatible Suzuki-Miyaura Cross Coupling Reaction.ACS medicinal chemistry letters · 2019Article
- Combination potentiator ('co-potentiator') therapy for CF caused by CFTR mutants, including N1303K, that are poorly responsive to single potentiators.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2018Article
- Comparative Effects of Chloride Channel Inhibitors on LRRC8/VRAC-Mediated Chloride Conductance.Frontiers in pharmacology · 2017Article
- Potentiators exert distinct effects on human, murine, and Xenopus CFTR.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- CFTR activator increases intestinal fluid secretion and normalizes stool output in a mouse model of constipation.Cellular and molecular gastroenterology and hepatology · 2016Article
- Generation and functional characterization of epithelial cells with stable expression of SLC26A9 Cl- channels.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop.The Journal of biological chemistry · 2016Article
- PharmGKB summary: very important pharmacogene information for CFTR.Pharmacogenetics and genomics · 2015Article
- Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis.Science translational medicine · 2014Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) Cl⁻ channel. We developed a phenotype-based high-throughput screen to identify small-molecule activators of human airway epithelial Ca²⁺-activated Cl⁻ channels (CaCCs) for CF therapy. Unexpectedly, screening of ∼110,000 synthetic small molecules revealed an amino-carbonitrile-pyrazole, C(act)-A1, that activated CFTR but not CaCC Cl⁻ conductance. C(act)-A1 produced large and sustained CFTR Cl⁻ currents in CFTR-expressing Fisher rat thyroid (FRT) cells and in primary cultures of human bronchial epithelial (HBE) cells, without increasing intracellular cAMP and in the absence of a cAMP agonist. C(act)-A1 produced linear whole-cell currents. C(act)-A1 also activated ΔF508-CFTR Cl⁻ currents in low temperature-rescued ΔF508-CFTR-expressing FRT cells and CF-HBE cells (from homozygous ΔF508 patients) in the absence of a cAMP agonist, and showed additive effects with forskolin. In contrast, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770) and genistein produced little or no ΔF508-CFTR Cl⁻ current in the absence of a cAMP agonist. In FRT cells expressing G551D-CFTR and in CF nasal polyp epithelial cells (from a heterozygous G551D/Y1092X-CFTR patient), C(act)-A1 produced little Cl⁻ current by itself but showed synergy with forskolin. The amino-carbonitrile-pyrazole C(act)-A1 identified here is unique among prior CFTR-activating compounds, as it strongly activated wild-type and ΔF508-CFTR in the absence of a cAMP agonist. Increasing ΔF508-CFTR Cl⁻ conductance by an "activator," as defined by activation in the absence of cAMP stimulation, provides a novel strategy for CF therapy that is different from that of a "potentiator," which requires cAMP elevation.
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