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

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Item Type:Article
Title:Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis
Creators Name:Campa, C.C. and Silva, R.L. and Margaria, J.P. and Pirali, T. and Mattos, M.S. and Kraemer, L.R. and Reis, D.C. and Grosa, G. and Copperi, F. and Dalmarco, E.M. and Lima-Júnior, R.C.P. and Aprile, S. and Sala, V. and Dal Bello, F. and Prado, D.S. and Alves-Filho, J.C. and Medana, C. and Cassali, G.D. and Tron, G.C. and Teixeira, M.M. and Ciraolo, E. and Russo, R.C. and Hirsch, E.
Abstract: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.
Keywords:Animals, Mice
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
Volume:9
Number:1
Page Range:5232
Date:12 December 2018
Official Publication:https://doi.org/10.1038/s41467-018-07698-6
PubMed:View item in PubMed

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