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Lookup NU author(s): Dr Lee Borthwick,
Professor Andrew Fisher
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2020, The Author(s).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.
Author(s): John AE, Graves RH, Pun KT, Vitulli G, Forty EJ, Mercer PF, Morrell JL, Barrett JW, Rogers RF, Hafeji M, Bibby LI, Gower E, Morrison VS, Man Y, Roper JA, Luckett JC, Borthwick LA, Barksby BS, Burgoyne RA, Barnes R, Le J, Flint DJ, Pyne S, Habgood A, Organ LA, Joseph C, Edwards-Pritchard RC, Maher TM, Fisher AJ, Gudmann NS, Leeming DJ, Chambers RC, Lukey PT, Marshall RP, Macdonald SJF, Jenkins RG, Slack RJ
Publication type: Article
Publication status: Published
Journal: Nature Communications
Online publication date: 16/09/2020
Acceptance date: 17/08/2020
Date deposited: 07/01/2021
ISSN (electronic): 2041-1723
Publisher: Nature Publishing Group
PubMed id: 32938936
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