The ávâ6 integrin plays a key role in the activation of transforming growth factor-â (TGFâ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule ávâ6 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 ávâ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFâ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the ávâ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages ávâ6, induces prolonged inhibition of TGFâ 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.
Administration, Inhalation Animals