The therapeutic potential of small-molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl^- channel

The cystic fibrosis transmembrane conductance regulator (CFTR) plays a pivotal role in fluid and electrolyte movements across ducts and tubes lined by epithelia. Loss of CFTR function causes the common life-limiting genetic disease cystic fibrosis (CF) and a spectrum of disorders termed CFTR-related diseases, while unphysiological CFTR activity characterises secretory diarrhoea and autosomal dominant polycystic kidney disease (ADPKD). The prevalence of these disorders argues persuasively that small-molecule CFTR modulators have significant therapeutic potential. Here, we discuss how knowledge and understanding of the CFTR Cl− channel, its physiological role and malfunction in disease led to the development of the CFTR potentiator ivacaftor, the first small molecule targeting CFTR approved as a treatment for CF. We consider the prospects for developing other therapeutics targeting directly CFTR including CFTR correctors to rescue the apical membrane expression of CF mutants, CFTR corrector-potentiators, dual-acting small-molecules to correct the processing and gating defects of F508del-CFTR, the commonest CF mutant and CFTR inhibitors to prevent fluid and electrolyte loss in secretory diarrhoea and cyst swelling in ADPKD. The success of ivacaftor provides impetus to other CFTR drug development programmes and a paradigm for the creation of therapeutics targeting the root cause of other genetic disorders.