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

Alison E. John, Rebecca H. Graves, Tao Pun, Giovanni Vitulli, Ellen J. Forty, Paul F. Mercer, Josie L. Morrell, John W. Barrett, Rebecca F. Rogers, Maryam Hafeji, Lloyd I. Bibby, Elaine Gower, Valerie S. Morrison, Yim Man, James A. Roper, Jeni C. Luckett, Lee A. Borthwick, Ben S. Barksby, Rachel A. Burgoyne, Rory BarnesJoelle Le, David J. Flint, Susan Pyne, Anthony Habgood, Louise A. Organ, Chitra Joseph, Rochelle C. Edwards-Pritchard, Toby M. Maher, Andrew J. Fisher, Natasja Staehr Gudmann, Diana J. Leeming, Rachel C. Chambers, Pauline T. Lukey, Richard P. Marshall, Simon J. F. Macdonald, Gisli Jenkins, Robert J. Slack

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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.
Original languageEnglish
Article number4659
Number of pages14
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 16 Sep 2020

Keywords

  • idiopathic pulmonary fibrosis
  • lung epithelial cells
  • abnormal wound healing

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