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

Author

Listed:
  • Alison E. John

    (University of Nottingham)

  • Rebecca H. Graves

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • K. Tao Pun

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • Giovanni Vitulli

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • Ellen J. Forty

    (University College London)

  • Paul F. Mercer

    (University College London)

  • Josie L. Morrell

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • John W. Barrett

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • Rebecca F. Rogers

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • Maryam Hafeji

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • Lloyd I. Bibby

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • Elaine Gower

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • Valerie S. Morrison

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • Yim Man

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • James A. Roper

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • Jeni C. Luckett

    (University of Nottingham)

  • Lee A. Borthwick

    (Newcastle University Biosciences Institute and Newcastle University Translational and Clinical Research Institute)

  • Ben S. Barksby

    (Newcastle University Biosciences Institute and Newcastle University Translational and Clinical Research Institute)

  • Rachel A. Burgoyne

    (Newcastle University Biosciences Institute and Newcastle University Translational and Clinical Research Institute)

  • Rory Barnes

    (Newcastle University Biosciences Institute and Newcastle University Translational and Clinical Research Institute)

  • Joelle Le

    (Drug Design and Selection - Molecular Design, Respiratory TAU, GlaxoSmithKline)

  • David J. Flint

    (University of Strathclyde)

  • Susan Pyne

    (University of Strathclyde)

  • Anthony Habgood

    (University of Nottingham)

  • Louise A. Organ

    (University of Nottingham)

  • Chitra Joseph

    (University of Nottingham)

  • Rochelle C. Edwards-Pritchard

    (University of Nottingham)

  • Toby M. Maher

    (NIHR Respiratory Clinical Research Facility, Royal Brompton Hospital
    Fibrosis Research Group, National Heart and Lung Institute, Imperial College)

  • Andrew J. Fisher

    (Newcastle University Biosciences Institute and Newcastle University Translational and Clinical Research Institute
    Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS, Foundation Trust)

  • Natasja Stæhr Gudmann

    (Nordic Bioscience A/S, Biomarkers and Research)

  • Diana J. Leeming

    (Nordic Bioscience A/S, Biomarkers and Research)

  • Rachel C. Chambers

    (University College London)

  • Pauline T. Lukey

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • Richard P. Marshall

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • Simon J. F. Macdonald

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

  • R. Gisli Jenkins

    (University of Nottingham)

  • Robert J. Slack

    (Fibrosis DPU, Respiratory TAU, GlaxoSmithKline)

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.

Suggested Citation

  • Alison E. John & Rebecca H. Graves & K. Tao Pun & Giovanni Vitulli & Ellen J. Forty & Paul F. Mercer & Josie L. Morrell & John W. Barrett & Rebecca F. Rogers & Maryam Hafeji & Lloyd I. Bibby & Elaine , 2020. "Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18397-6
    DOI: 10.1038/s41467-020-18397-6
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    Cited by:

    1. Anindya Roy & Lei Shi & Ashley Chang & Xianchi Dong & Andres Fernandez & John C. Kraft & Jing Li & Viet Q. Le & Rebecca Viazzo Winegar & Gerald Maxwell Cherf & Dean Slocum & P. Daniel Poulson & Garret, 2023. "De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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