Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis.
Administration, Inhalation
Animals
Antigens, Neoplasm
/ metabolism
Bleomycin
/ toxicity
Butyrates
/ administration & dosage
Collagen
/ metabolism
Disease Models, Animal
Epithelial Cells
/ drug effects
Humans
Idiopathic Pulmonary Fibrosis
/ chemically induced
Integrins
/ antagonists & inhibitors
Male
Mice, Inbred C57BL
Molecular Docking Simulation
Naphthyridines
/ administration & dosage
Pyrazoles
/ administration & dosage
Pyrrolidines
/ administration & dosage
Small Molecule Libraries
/ chemistry
Tomography, Emission-Computed, Single-Photon
Transforming Growth Factor beta
/ metabolism
Translational Research, Biomedical
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 09 2020
16 09 2020
Historique:
received:
07
11
2018
accepted:
17
08
2020
entrez:
17
9
2020
pubmed:
18
9
2020
medline:
3
10
2020
Statut:
epublish
Résumé
The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.
Identifiants
pubmed: 32938936
doi: 10.1038/s41467-020-18397-6
pii: 10.1038/s41467-020-18397-6
pmc: PMC7494911
doi:
Substances chimiques
Antigens, Neoplasm
0
Butyrates
0
GSK3008348
0
Integrins
0
Naphthyridines
0
Pyrazoles
0
Pyrrolidines
0
Small Molecule Libraries
0
Transforming Growth Factor beta
0
integrin alphavbeta6
0
Bleomycin
11056-06-7
Collagen
9007-34-5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4659Subventions
Organisme : Department of Health
ID : CS-2013-13-017
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0901226
Pays : United Kingdom
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