Pharmacological Rescue of Mutant CFTR Function for the Treatment of Cystic Fibrosis

Abstract

The vast majority of morbidity and mortality in cystic fibrosis (CF) patients is due to lung disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR). CFTR is a PKA-regulated anion channel localized in the apical membrane of bronchial epithelia where it controls salt and fluid regulation to facilitate bacteria clearance. There are over 1000 disease-causing mutations in the gene encoding CFTR and, depending on the type of mutation, the cell surface density and/or functional activity of CFTR in the apical membrane is reduced. A therapeutic strategy for the treatment of lung disease in CF patients is to use pharmacological agents that increase mutant CFTR-mediated anion secretion. High-throughput screening strategies have identified multiple chemotypes that increase mutant CFTR-mediated anion secretion. These chemotypes can be grouped into two classes based on their mode of action. The first class is known as CFTR correctors because they correct the processing and trafficking of CFTR to increases its cell surface density. The second class is known as CFTR potentiators as they potentiate the amount of anion secretion through CFTR at the cell surface. In vivo analysis of CFTR activity in CF patients indicates that it is correlated with the severity of lung disease and supports the hypothesis that CFTR modulators that restore mutant CFTR activity to >10% of wild-type-CFTR would improve lung function. The use of high-throughput screening and medicinal chemistry optimization to improve the efficacy, potency, and pharmaceutical properties of the multiple potentiator or corrector scaffolds identified to date offers a promising approach for the treatment of CF by directly targeting the root cause of the disease.