Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis
Open accessAbstract
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.
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IPF PCLSs have been used to evaluate the therapeutic effect, pharmacology, and mechanism of action of potential antifibrotic agents, including GSK2126458 (omipalisib), CZ415, GSK3008348, and EGCG.
“IPF PCLSs have been used to evaluate the therapeutic effect, pharmacology, and mechanism of action of potential antifibrotic agents, including the PI3K/AKT/mTOR inhibitor, GSK2126458 (omipalisib) (Mercer et al., 2016), the dual ATP-competitive mTOR inhibitor CZ415 (Woodcock et al., 2019), the αvβ6 inhibitor GSK3008348 (John et al., 2020), and the antifibrotic agent epigallocatechin gallate (EGCG”
From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as John et al., 2020
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- Authors
- John, A. E., Graves, R. H., Pun, K. T., Vitulli, G., Forty, E. J., Mercer, P. F., Morrell, J. L., Barrett, J. W., Rogers, R. F., Hafeji, M., Bibby, L. I., Gower, E., Morrison, V. S., Man, Y., Roper, J. A., Luckett, J. C., Borthwick, L. A., Barksby, B. S., Burgoyne, R. A., Barnes, R., Le, J., Flint, D. J., Pyne, S., Habgood, A., Organ, L. A., Joseph, C., Edwards-Pritchard, R. C., Maher, T. M., Fisher, A. J., Gudmann, N. S., Leeming, D. J., Chambers, R. C., Lukey, P. T., Marshall, R. P., Macdonald, S. J. F., Jenkins, R. G., & Slack, R. J.
- Affiliations
- University of Nottingham (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- University College London (GB)
- Newcastle University (GB)
- University of Strathclyde (GB)
- Royal Brompton Hospital (GB)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Nordic Bioscience (Denmark) (DK)
- ORCID
- John, Alison E.
- Graves, Rebecca H.
- Pun, K. Tao
- Vitulli, Giovanni
- Forty, Ellen J.
- Rogers, Rebecca F.
- Hafeji, Maryam
- Bibby, Lloyd I.
- Man, Yim
- Roper, James A.
- Luckett, Jeni C.
- Borthwick, Lee A.
- Barnes, Rory
- Le, Joelle
- Pyne, Susan
- Habgood, Anthony
- Organ, Louise A.
- Joseph, Chitra
- Edwards-Pritchard, Rochelle C.
- Maher, Toby M.
- Fisher, Andrew J.
- Gudmann, Natasja Stæhr
- Leeming, Diana J.
- Chambers, Rachel C.
- Lukey, Pauline T.
- Marshall, Richard P.
- Macdonald, Simon J. F.
- Jenkins, R. Gisli
- Slack, Robert J.
- Venue
- Nature Communications
- Published
- 2020-09-16
- Volume
- 11
- Issue
- 1
- Pages
- 4659-4659
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7494911
- OpenAlex
- W3087286534
- Cited by
- 131
- References
- 47
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 23 · 2023: 22 · 2022: 24 · 2021: 19 · 2020: 1
- FWCI
- 9.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Strathprints: The University of Strathclyde institutional repository (University of Strathclyde) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- GlaxoSmithKline
- National Institute for Health and Care Research (CS-2013-13-017)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- idiopathic pulmonary fibrosis, integrin αvβ6, RGD mimetics, TGF-beta signaling, antifibrotic therapy, target engagement, integrin internalization, lysosomal degradation, bleomycin-induced lung fibrosis, collagen deposition, pharmacodynamics
- MeSH terms
- Administration, Inhalation, Animals, Antigens, Neoplasm, Bleomycin, Butyrates, Collagen, Disease Models, Animal, Epithelial Cells, Humans, Male, Mice, Inbred C57BL, Naphthyridines, Pyrazoles, Pyrrolidines, Tomography, Emission-Computed, Single-Photon, Integrins, Transforming Growth Factor beta, Small Molecule Libraries, Idiopathic Pulmonary Fibrosis, Translational Research, Biomedical, Molecular Docking Simulation
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