CFTR inhibitors

• Published in: Current pharmaceutical design Vol. 19; no. 19; p. 3529
• Main Authors: Verkman, Alan S, Synder, David, Tradtrantip, Lukmanee, Thiagarajah, Jay R, Anderson, Marc O
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 2013
• Subjects: Animals; Cystic Fibrosis - drug therapy; Cystic Fibrosis - genetics; Cystic Fibrosis - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - antagonists & inhibitors; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Drug Discovery; Glycine - analogs & derivatives; Glycine - chemistry; Glycine - pharmacology; High-Throughput Screening Assays; Humans; Models, Molecular; Molecular Structure; Mutation; Polycystic Kidney Diseases - drug therapy; Polycystic Kidney Diseases - genetics; Polycystic Kidney Diseases - metabolism; Quinoxalines - chemistry; Quinoxalines - pharmacology; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Thiazolidinediones - chemistry; Thiazolidinediones - pharmacology
• DOI: 10.2174/13816128113199990321

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cAMP-regulated Cl- channel whose major function is to facilitate epithelial fluid secretion. Loss-of-function mutations in CFTR cause the genetic disease cystic fibrosis. CFTR is required for transepithelial fluid transport in certain secretory diarrheas, such as cholera, and for cyst expansion in autosomal dominant polycystic kidney disease. High-throughput screening has yielded CFTR inhibitors of the thiazolidinone, glycine hydrazide and quinoxalinedione chemical classes. The glycine hydrazides target the extracellular CFTR pore, whereas the thiazolidinones and quinoxalinediones act at the cytoplasmic surface. These inhibitors have been widely used in cystic fibrosis research to study CFTR function at the cell and organ levels. The most potent CFTR inhibitor has IC50 of approximately 4 nM. Studies in animal models support the development of CFTR inhibitors for antisecretory therapy of enterotoxin-mediated diarrheas and polycystic kidney disease.