Ivacaftor is a potent and selective potentiator of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) that targets F508del-CFTR and G551D-CFTR (EC50 values are 25 nM and 100 nM, respectively); its potentiation activity depends on the level of CFTR phosphorylation. Ivacaftor reversibly binds to wild type (WT-CFTR) and G551D-CFTR mutants, increasing the open probability via an ATP-independent mechanism, and enhances cAMP/PKA-signaling mediated gating activity for both WT-CFTR and G551D-CFTR mutants. In cultured human CF bronchial epithelia with G551D/F508del mutations, Ivacaftor increases Forskolin (Cat. No. 1099)-induced transepithelial current (EC50 = 236 nM) and increases chloride secretion by 10-fold. Also rescues endothelial CFTR expression and function and prevents endothelial barrier failure and protein leak in human pulmonary microvascular endothelial cells. Ivacaftor is orally bioavailable.
