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Nat Commun. 2018 Dec 12;9(1):5232. doi: 10.1038/s41467-018-07698-6.

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

Author information

1
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126, Torino, Italy.
2
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, 14049-900, Ribeirao Preto, Brazil.
3
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro", Largo Donegani 2, 28100, Novara, Italy.
4
Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais/UFMG, Avenida Antonio Carlos 6627, Belo Horizonte, 31270-901, Brazil.
5
Laboratory of Comparative Pathology, Department of General Pathology Institute of Biological Sciences, Universidade Federal de Minas Gerais/UFMG, Avenida Antonio Carlos 6627, Belo Horizonte, 31270-901, Brazil.
6
Department of Clinical Analysis, Universidade Federal de Santa Catarina/UFSC, Rua Delfino Conti, S/N, Florianopolis, 88040-370, Brazil.
7
Laboratory of Pharmacology of Inflammation and Cancer, Department of Physiology and Pharmacology, Universidade Federal do Ceará/UFC, Rua Cel Nunes de Melo 1127, Fortaleza, 60430-270, Brazil.
8
Department of Molecular Biotechnology and Health Sciences, Mass Spectrometry Unit, University of Torino, Via Giuria 5, 10125, Torino, Italy.
9
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro", largo Donegani 2, 28100, Novara, Italy.
10
Kither Biotech S.r.l., Via Nizza 52, 10126, Torino, Italy.
11
Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais/UFMG, Avenida Antonio Carlos 6627, Belo Horizonte, 31270-901, Brazil.
12
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126, Torino, Italy. Elisa.Ciraolo@mdc-berlin.de.
13
Max Delbrück Center for Molecular Medicine, 13125, Berlin, Germany. Elisa.Ciraolo@mdc-berlin.de.

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.

PMID:
30542075
PMCID:
PMC6290777
DOI:
10.1038/s41467-018-07698-6
[Indexed for MEDLINE]
Free PMC Article

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