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

The alpha v beta 6 integrin plays a key role in the activation of transforming growth factor-beta (TGF beta), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule alpha v beta 6 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 alpha v beta 6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGF beta signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the alpha v beta 6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages alpha v beta 6, induces prolonged inhibition of TGF beta 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 alpha v beta 6 integrin is key in activating the pro-fibrotic cytokine TGF beta in idiopathic pulmonary fibrosis. Here, the authors show an inhaled small molecule alpha v beta 6 inhibitor GSK3008348 induces prolonged inhibition of TGF beta signaling pathways in human and murine models of lung fibrosis via alpha v beta 6 degradation.