Cystic Fibrosis (CF) is an obstructive and chronic disorder that affects the mucosal linings of multiple organs. CF results from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) protein, with the most prominent mutation being the deletion of phenylalanine 508 or the F508del mutation. The FDA-approved drug Lumacaftor (VX-809) has been found to partially correct the folding defect of F508del-CFTR. However VX-809 produces only modest gains in lung function of CF patients, and drugs which more effectively improve the folding of F508del-CFTR are necessary for the next generation of improvement in CF therapy. In situ click chemistry (isCC) represents a drug discovery strategy that uses the biological target to catalyze the azide-alkyne cycloaddition reaction to form triazole containing small molecules that inherently have strong interactions with the target of interest. We report the synthesis and biological evaluation of analogs of VX-809 that are compatible with the in situ click chemistry approach. Several isCC-compatible VX-809 analogs were found to be active correctors of F508del-CFTR, making possible further studies to test the implementation of the isCC strategy to discover improved correctors for F508del-CFTR.

Discovery of <i>in situ</i> click chemistry compatible analogs of F508del-CFTR corrector VX-809

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

Discovery of in situ click chemistry compatible analogs of F508del-CFTR corrector VX-809