Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

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John, Alison E. and Graves, Rebecca H. and Pun, Tao and Vitulli, Giovanni and Forty, Ellen J. and Mercer, Paul F. and Morrell, Josie L. and Barrett, John W. and Rogers, Rebecca F. and Hafeji, Maryam and Bibby, Lloyd I. and Gower, Elaine and Morrison, Valerie S. and Man, Yim and Roper, James A. and Luckett, Jeni C. and Borthwick, Lee A. and Barksby, Ben S. and Burgoyne, Rachel A. and Barnes, Rory and Le, Joelle and Flint, David J. and Pyne, Susan and Habgood, Anthony and Organ, Louise A. and Joseph, Chitra and Edwards-Pritchard, Rochelle C. and Maher, Toby M. and Fisher, Andrew J. and Gudmann, Natasja Staehr and Leeming, Diana J. and Chambers, Rachel C. and Lukey, Pauline T. and Marshall, Richard P. and Macdonald, Simon J. F. and Jenkins, Gisli and Slack, Robert J. (2020) Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis. Nature Communications, 11 (1). 4659. ISSN 2041-1723 (https://doi.org/10.1038/s41467-020-18397-6)

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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 diseaserelated 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.

ORCID iDs

John, Alison E., Graves, Rebecca H., Pun, 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 ORCID logoORCID: https://orcid.org/0000-0002-6608-9584, Habgood, Anthony, Organ, Louise A., Joseph, Chitra, Edwards-Pritchard, Rochelle C., Maher, Toby M., Fisher, Andrew J., Gudmann, Natasja Staehr, Leeming, Diana J., Chambers, Rachel C., Lukey, Pauline T., Marshall, Richard P., Macdonald, Simon J. F., Jenkins, Gisli and Slack, Robert J.;
CORE (COnnecting REpositories)