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

Carlo C. Campa, Rangel L. Silva, Jean P. Margaria, Tracey Pirali, Matheus S. Mattos, Lucas R. Kraemer, Diego C. Reis, Giorgio Grosa, Francesca Copperi, Eduardo M. Dalmarco, Roberto C. P. Lima-Júnior, Silvio Aprile, Valentina Sala, Federica Dal Bello, Douglas Silva Prado, Jose Carlos Alves-Filho, Claudio Medana, Geovanni D. Cassali, Gian Cesare Tron, Mauro M. Teixeira, Elisa Ciraolo (), Remo C. Russo and Emilio Hirsch
Additional contact information
Carlo C. Campa: University of Torino
Rangel L. Silva: University of Torino
Jean P. Margaria: University of Torino
Tracey Pirali: Università degli Studi del Piemonte Orientale “A. Avogadro”
Matheus S. Mattos: Universidade Federal de Minas Gerais/UFMG
Lucas R. Kraemer: Universidade Federal de Minas Gerais/UFMG
Diego C. Reis: Universidade Federal de Minas Gerais/UFMG
Giorgio Grosa: Università degli Studi del Piemonte Orientale “A. Avogadro”
Francesca Copperi: University of Torino
Eduardo M. Dalmarco: Universidade Federal de Santa Catarina/UFSC
Roberto C. P. Lima-Júnior: University of Torino
Silvio Aprile: Università degli Studi del Piemonte Orientale “A. Avogadro”
Valentina Sala: University of Torino
Federica Dal Bello: University of Torino
Douglas Silva Prado: University of São Paulo
Jose Carlos Alves-Filho: University of São Paulo
Claudio Medana: University of Torino
Geovanni D. Cassali: Universidade Federal de Minas Gerais/UFMG
Gian Cesare Tron: Università degli Studi del Piemonte Orientale “A. Avogadro”
Mauro M. Teixeira: Universidade Federal de Minas Gerais/UFMG
Elisa Ciraolo: University of Torino
Remo C. Russo: Universidade Federal de Minas Gerais/UFMG
Emilio Hirsch: University of Torino

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07698-6

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