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Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis.

Carlo C CampaRangel L SilvaJean P MargariaTracey PiraliMatheus S MattosLucas R KraemerDiego C ReisGiorgio GrosaFrancesca CopperiEduardo M DalmarcoRoberto C P Lima-JúniorSilvio AprileValentina SalaFederica Dal BelloDouglas Silva PradoJosé Carlos Alves FilhoClaudio MedanaGeovanni D CassaliGian Cesare TronMauro M TeixeiraElisa CiraoloRemo C RussoEmilio Hirsch
Published in: Nature communications (2018)
PI3K activation plays a central role in the development of pulmonary inflammation and tissue remodeling. PI3K inhibitors may thus offer an improved therapeutic opportunity to treat non-resolving lung inflammation but their action is limited by unwanted on-target systemic toxicity. Here we present CL27c, a prodrug pan-PI3K inhibitor designed for local therapy, and investigate whether inhaled CL27c is effective in asthma and pulmonary fibrosis. Mice inhaling CL27c show reduced insulin-evoked Akt phosphorylation in lungs, but no change in other tissues and no increase in blood glycaemia, in line with a local action. In murine models of acute or glucocorticoid-resistant neutrophilic asthma, inhaled CL27c reduces inflammation and improves lung function. Finally, inhaled CL27c administered in a therapeutic setting protects from bleomycin-induced lung fibrosis, ultimately leading to significantly improved survival. Therefore, local delivery of a pan-PI3K inhibitor prodrug reduces systemic on-target side effects but effectively treats asthma and irreversible pulmonary fibrosis.
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