Discovery and Development of CFTR Modulators for the Treatment of Cystic Fibrosis.

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which regulates ion and fluid transport across epithelial cells. Mutations lead to complications, with life-limiting lung disease being the most severe manifestation. Traditional treatments focused on managing symptoms, but advances in understanding CF's molecular basis led to small-molecule CFTR modulators. Ivacaftor, which is a potentiator, was approved for gating mutations. Dual combinations like ivacaftor/lumacaftor and ivacaftor/tezacaftor brought together a potentiator and a class 1 corrector for F508del homozygous patients. Triple-combination CFTR modulators, including ivacaftor/tezacaftor/elexacaftor with an additional class 2 corrector, are now the standard of care for most CF patients, transforming the outlook for this disease. These drugs stabilize and potentiate the CFTR protein, improving lung function, sweat chloride levels, quality of life, and survival. This Perspective discusses CFTR structure and mutations, biological assays, medicinal chemistry research in identifying CFTR modulators, and clinical data of these agents.