Cystic Fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is a life-limiting inherited disorder affecting 70,000 individuals worldwide (~30,000 in the US) with annual health care costs of at least $1.8 billion. Recent advances in new CF drug development have led to approval of ivacaftor (Kalydeco or VX770), lumacaftor/ivacaftor combination (Orkambi or VX809+ VX770), and tezacaftor/ivacaftor (Symdeko or VX661+VX770) under review). Although these represent exciting translational successes for the CF community, their clinical efficacy for patients with CF is suboptimal and falls within the range of established symptomatic therapies. Furthermore, persistent airway infection and inflammation may undermine benefits of current CFTR modulators, including enhanced degradation of corrected Phe508del-CFTR by Pseudomonas aeruginosa virulence factors. Finally, the high cost of CFTR modulators limits access of CF patients to CFTR modulators, highlighting the critical need for ongoing effective drug development. Our combinatorial bioinformatics analysis using CF patient gene expression data coupled with compound screening and in vitro assays identified saracatinib (AZD0530), a known src family kinase (SFK) inhibitor, as a candidate CFTR modulator eliciting a strong rescue of F508del-CFTR comparable to that of approved CFTR modulators. Several prior studies have also demonstrated anti-inflammatory and anti-infective activity of saracatinib. This proposal is designed to determine if saracatinib is a candidate therapeutic for CF, and its primary mechanism of action relevant to CF lung disease in vivo. Our three specific aims are: aim 1: Establish saracatinib as a pre-clinical CFTR modulator (UG3); aim 2: Evaluate the effect of saracatinib on infection and inflammation associated with CF (UG3); and aim 3: Prepare for a clinical trial to test effectiveness of saracatinib for CF therapy (UH3). The ultimate goal of this project is to provide evidence in support of a multi-center clinical trial of saracatinib in CF.