Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis
| Autor: | Natasja Stæhr Gudmann, Richard P. Marshall, Jeni Luckett, Rebecca F. Rogers, Robert J. Slack, Simon J. F. Macdonald, Diana Julie Leeming, Rachel C. Chambers, Joelle Le, Pauline T. Lukey, Anthony Habgood, Paul F. Mercer, Rachel A. Burgoyne, Ben S. Barksby, Lloyd I. Bibby, Yim Man, Maryam Hafeji, Andrew J. Fisher, David J. Flint, Toby M. Maher, Louise Organ, Susan Pyne, Lee A. Borthwick, James A. Roper, Valerie S. Morrison, Alison E. John, Giovanni Vitulli, Rebecca H. Graves, Rochelle C. Edwards-Pritchard, R. Gisli Jenkins, John Barrett, Josie Morrell, K. Tao Pun, Elaine Gower, Rory Barnes, Ellen J. Forty, Chitra Joseph |
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| Přispěvatelé: | National Institute for Health Research |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Integrins Pyrrolidines General Physics and Astronomy Pharmacology INTEGRIN-ALPHA-V-BETA-6 NINTEDANIB Translational Research Biomedical Idiopathic pulmonary fibrosis 0302 clinical medicine Transforming Growth Factor beta Fibrosis Medicine lcsh:Science Internalization media_common Multidisciplinary PIRFENIDONE respiratory system Small molecule Multidisciplinary Sciences Molecular Docking Simulation Butyrates medicine.anatomical_structure 030220 oncology & carcinogenesis Science & Technology - Other Topics Collagen TYROSINE KINASE INHIBITOR media_common.quotation_subject Science MODELS Article General Biochemistry Genetics and Molecular Biology RS Small Molecule Libraries Bleomycin 03 medical and health sciences Mediator Antigen Antigens Neoplasm Administration Inhalation Animals Humans Naphthyridines Tomography Emission-Computed Single-Photon Respiratory tract diseases Science & Technology Lung business.industry Epithelial Cells General Chemistry EFFICACY medicine.disease Idiopathic Pulmonary Fibrosis respiratory tract diseases Mice Inbred C57BL Disease Models Animal 030104 developmental biology Pharmacodynamics Pyrazoles lcsh:Q business Transforming growth factor |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. The αvβ6 integrin is key in activating the pro-fibrotic cytokine TGFβ in idiopathic pulmonary fibrosis. Here, the authors show an inhaled small molecule αvβ6 inhibitor GSK3008348 induces prolonged inhibition of TGFβ signaling pathways in human and murine models of lung fibrosis via αvβ6 degradation. |
| Databáze: | OpenAIRE |
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