Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment

• Published in: Scientific reports Vol. 11; no. 1; p. 19810
• Main Authors: Shaughnessy, Ciaran A, Zeitlin, Pamela L, Bratcher, Preston E
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 06.10.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Aminophenols - pharmacology; Benzodioxoles - pharmacology; Cells, Cultured; Chloride Channel Agonists - pharmacology; Cystic fibrosis; Cystic Fibrosis - drug therapy; Cystic Fibrosis - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Drug Combinations; Humans; Indoles - pharmacology; Lung diseases; Mutation; Pharmacology; Protein folding; Pyrazoles - pharmacology; Pyridines - pharmacology; Pyrrolidines - pharmacology; Quinolines - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-99184-1

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to early death due to progressive lung disease. The development of small-molecule modulators that directly interact with CFTR to aid in protein folding ("correctors") and/or increase channel function ("potentiators") have proven to be highly effective in the therapeutic treatment of CF. Notably, incorporation of the next-generation CFTR corrector, elexacaftor, into a triple combination therapeutic (marketed as Trikafta) has shown tremendous clinical promise in treating CF caused by F508del-CFTR. Here, we report on a newly-described role of elexacaftor as a CFTR potentiator. We explore the acute and chronic actions, pharmacology, and efficacy of elexacaftor as a CFTR potentiator in restoring function to multiple classes of CFTR mutations. We demonstrate that the potentiating action of elexacaftor exhibits multiplicative synergy with the established CFTR potentiator ivacaftor in rescuing multiple CFTR class defects, indicating that a new combination therapeutic of ivacaftor and elexacaftor could have broad impact on CF therapies.