Inhalation of the prodrug PI3K inhibitor CL27cimproves lung function in asthma andfibrosis

• Autor(a) principal: Campa, Carlo C.
• Data de Publicação: 2018
• Outros Autores: Silva, Rangel L., Margaria, Jean P., Piral, Tracey, Mattos, Matheus S., Kraemer, Lucas R., Reis, Diego C., Grosa, Giorgio, Copperi, Francesca, Dalmarco, Eduardo M., Lima-Júnior, Roberto C.P., Aprile, Silvio, Sala, Valentina, Bello, Bello, Prado, Douglas Silva, Alves-Filho, Jose Carlos, Medana, Claudio, Cassali, Geovanni D., Tron, Gian Cesare, Teixeira, Mauro M., Ciraolo, Elisa, Russo, Remo C., Hirsch, Emilio
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da Universidade Federal do Ceará (UFC)
• Texto Completo: http://www.repositorio.ufc.br/handle/riufc/40253
• topic: Asma; Asthma; Fibrose; Fibrosis

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.