Lipophilicity of the Cystic Fibrosis Drug, Ivacaftor (VX-770), and Its Destabilizing Effect on the Major CF-causing Mutation: F508del

• DOI: 10.1124/mol.118.112177
• Publication Date: 2018-06-14T15:55:12Z
• Authors: Stephanie Chin; Maurita Hung; Amy Won; Yu-Sheng Wu; Saumel Ahmadi; Donghe Yang; Salma Elmallah; Krimo Toutah; C. Michael Hamilton; Robert N. Young; Russell D. Viirre; Christopher M. Yip; Christine E. Bear
• Keywords: Ivacaftor; Lipophilicity

Deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) is the most common (CF)-causing mutation. Recently, ORKAMBI, a combination therapy that includes corrector processing defect F508del-CFTR (lumacaftor or VX-809) and potentiator channel activity (ivacaftor VX-770), was approved for CF patients homozygous this However, clinical studies revealed effect ORKAMBI on lung function modest it proposed relates to negative impact VX-770 stability F508del-CFTR. In current studies, we showed 10 <i>μ</i>M correlated with its inhibitory VX-809-mediated correction interface between second membrane spanning domain first nucleotide binding bearing F508del. Interestingly, found exerted similar other localized solute carriers (SLC26A3, SLC26A9, SLC6A14), suggesting not specific We determined relative destabilizing panel derivatives their predicted lipophilicity. Polarized total internal reflection fluorescence microscopy supported lipid bilayer model shows VX-770, less lipophilic derivative, increased fluidity reorganized membrane. summary, our findings show there potential nonspecific effects suggest may account VX-809- rescued