Cystic fibrosis (CF) leads to chronic illness, disability, and early death. Recurrent pulmonary infections are lethal owing to growth of bacteria and other microorganisms in the abnormally viscous mucus. Antibiotics, mucolytics, and anti-inflammatory agents, are useful only in treating some CF effects. Recently, however, ivacaftor (a.k.a. VX-770 or Kalydeco), which addresses the underlying cause of CF, was approved by the FDA. Unfortunately, it is ineffective in a majority of patients. The underlying cause of CF is a mutatio of the cystic fibrosis transmembrane conductance regulator (CFTR), which normally localizes to the cell membrane and controls salt levels. In CF, a mutation decreases the amount or activity of CFTR, and the resultant salt dysregulation leads to CF pathologies. The primary mutation (> 90% in the US and ~75% worldwide) is ?F508, deletion of a single phenylalanine residue in CFTR. ?F508 causes improper folding of CFTR, most of which is degraded in the endoplasmic reticulum (ER) and does not reach the cell membrane. CFTR?F508 is partially functional if it can be localized to the membrane, and corrector drugs such as VX-809/lumacaftor are being developed to promote trafficking of mutant CFTR to the cell surface. Additional ways of increasing the levels, trafficking, and/or functionality of CFTR?F508 are being sought by intervening in various cellular pathways that regulate proteins, including the ubiquitin/proteasome pathway. Misfolded CFTR?F508 is ubiquitylated by the ubiquitin E3 ligase gp78 and degraded via ERAD (endoplasmic reticulum associated protein degradation), decreasing its cellular level. Knockdown of gp78 leads to dramatically increased levels of CFTR?F508 in cells and increases chloride transport. Thus gp78 inhibition should increase the amount of CFTR at the cell surface and may be useful alone or combined with correctors such as VX-809. In phase I, small molecule inhibitors of gp78 were identified and their ability to increase levels of functional CFTR, as judged by cellular assays, demonstrated. One of these hits (GP1) increased the level of core glycosylated CFTR?F508 and, when combined with VX-809, increased the level of functional CFTR?F508 in cells, providing further validation of gp78 as a target for the treatment of CF. In Phase II, GP1 and additional hit compounds will be improved by medicinal chemistry optimization, analyzed by in vitro and cell-based secondary assays, and tested in animal models for drug metabolism/pharmacokinetic properties, with the goal of identifying potent and selective lead compounds with efficacy as therapeutic agents for cystic fibrosis.