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

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.

• Authors: 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, Emilio Hirsch
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 5232 (12 12 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 30542075 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzene Derivatives
• CL27c
• Enzyme Inhibitors
• Esters
• Phosphoinositide-3 Kinase Inhibitors
• Bleomycin
• Ovalbumin
• Proto-Oncogene Proteins c-akt

Topics

• Administration, Inhalation
• Animals
• Asthma (chemically induced, drug therapy, pathology)
• Benzene Derivatives (administration & dosage, therapeutic use)
• Bleomycin (toxicity)
• Disease Models, Animal
• Enzyme Inhibitors (administration & dosage, therapeutic use)
• Esters (administration & dosage, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Ovalbumin (toxicity)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pulmonary Fibrosis (chemically induced, drug therapy, pathology)