Translational pharmacology of an inhaled small molecule \u03b1v\u03b26 integrin inhibitor for idiopathic pulmonary fibrosis

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

doi:10.1038/s41467-020-18397-6

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.

Highlights

The αvβ[6] 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)
GSK3008348 resides in a distinct niche, in the current IPF therapeutic pipeline space, and as one of the highest affinity integrin inhibitors that has been developed in the field of small and large molecule drug discovery[14]
The aim of this study was to fully characterize GSK3008348 and generate translational drug discovery biomarkers that will facilitate the performance of future clinical trials

Summary

Introduction

The αvβ[6] 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). In the murine bleomycin-induced model of lung fibrosis, GSK3008348 engages αvβ[6] integrins, inhibits the activation of TGFβ with a prolonged duration of action, and reduces lung fibrotic end points including collagen deposition and serum C3M levels, a clinically relevant marker of IPF disease progression. These studies describe an exemplar pathway for the development of an inhaled αvβ[6] integrin inhibitor, highlighting the potential of inhaled GSK3008348 as an anti-fibrotic therapy

Objectives

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Results

Conclusion