Translational pharmacology of an inhaled small molecule ?v?6 integrin inhibitor for idiopathic pulmonary fibrosis.
Ontology highlight
ABSTRACT: The ?v?6 integrin plays a key role in the activation of transforming growth factor-? (TGF?), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule ?v?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 ?v?6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGF? signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the ?v?6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages ?v?6, induces prolonged inhibition of TGF? 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.
SUBMITTER: John AE
PROVIDER: S-EPMC7494911 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
ACCESS DATA