Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis
Alison E. John, Rebecca H. Graves, Kwok‐Tao Pun, Giovanni Vitulli, Ellen Forty, Paul F. Mercer, Josie Morrell, John W. Barrett, Rebecca F. Rogers, Maryam Hafeji, Lloyd I. Bibby, Elaine Gower, Valerie S. Morrison, Yim Man, James A. Roper, Jeni Luckett, Lee A. Borthwick, Ben S. Barksby, Rachel A. Burgoyne, Rory Barnes, Joelle Le, David J. Flint, Susan Pyne, Anthony Habgood, Louise Organ, Chitra Joseph, Rochelle C. Edwards-Pritchard, Toby M. Maher, Andrew J. Fisher, N.S. Gudmann, Diana Julie Leeming, Rachel C. Chambers, Pauline T. Lukey, Richard P. Marshall, Simon J. F. Macdonald, Gísli Jenkins, Robert J. Slack
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.