Objectives: KALYDECO (ivacaftor/VX-770), a potentiator that enhances channel gating of wild-type cystic fibrosis transmembrane conductance regulator (CFTR) protein and certain CFTR gating mutants was first approved to treat Cystic Fibrosis (CF). Thereafter, Orkambi, a combination of ivacaftor and the trafficking corrector lumacaftor was approved for patients with homozygous F508del mutation. Unfortunately, ORKAMBI mediates modest and variable clinical responses which relates to a negative impact of VX-770 on the metabolic stability of F508del-CFTR. VX-770 was also shown to exert a negative effect on the stability of other membrane solute carriers. The destabilizing effect of VX-770 also correlated with its predicted lipophilicity, suggesting the need for discovery and optimization of efficacious potentiators to maximize the clinical benefit in CF.