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

Authors

  • C.C. Campa
  • R.L. Silva
  • J.P. Margaria
  • T. Pirali
  • M.S. Mattos
  • L.R. Kraemer
  • D.C. Reis
  • G. Grosa
  • F. Copperi
  • E.M. Dalmarco
  • R.C.P. Lima-Júnior
  • S. Aprile
  • V. Sala
  • F. Dal Bello
  • D.S. Prado
  • J.C. Alves-Filho
  • C. Medana
  • G.D. Cassali
  • G.C. Tron
  • M.M. Teixeira
  • E. Ciraolo
  • R.C. Russo
  • E. Hirsch

Journal

  • Nature Communications

Citation

  • Nat Commun 9 (1): 5232

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.


DOI

doi:10.1038/s41467-018-07698-6