학술논문
Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis
Document Type
Original Paper
Author
John, Alison E.; Graves, Rebecca H.; Pun, K. Tao; Vitulli, Giovanni; Forty, Ellen J.; Mercer, Paul F.; Morrell, Josie L.; Barrett, John W.; Rogers, Rebecca F.; Hafeji, Maryam; Bibby, Lloyd I.; Gower, Elaine; Morrison, Valerie S.; Man, Yim; Roper, James A.; Luckett, Jeni C.; Borthwick, Lee A.; Barksby, Ben S.; Burgoyne, Rachel A.; Barnes, Rory; Le, Joelle; Flint, David J.; Pyne, Susan; Habgood, Anthony; Organ, Louise A.; Joseph, Chitra; Edwards-Pritchard, Rochelle C.; Maher, Toby M.; Fisher, Andrew J.; Gudmann, Natasja Stæhr; Leeming, Diana J.; Chambers, Rachel C.; Lukey, Pauline T.; Marshall, Richard P.; Macdonald, Simon J. F.; Jenkins, R. Gisli; Slack, Robert J.
Source
Nature Communications. 11(1)
Subject
Language
English
ISSN
2041-1723
Abstract
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.
The αvβ6 integrin is key in activating the pro-fibrotic cytokine TGFβ in idiopathic pulmonary fibrosis. Here, the authors show an inhaled small molecule αvβ6 inhibitor GSK3008348 induces prolonged inhibition of TGFβ signaling pathways in human and murine models of lung fibrosis via αvβ6 degradation.
The αvβ6 integrin is key in activating the pro-fibrotic cytokine TGFβ in idiopathic pulmonary fibrosis. Here, the authors show an inhaled small molecule αvβ6 inhibitor GSK3008348 induces prolonged inhibition of TGFβ signaling pathways in human and murine models of lung fibrosis via αvβ6 degradation.