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A high content screen for mucin-1-reducing compounds identifies fostamatinib as a candidate for rapid repurposing for acute lung injury
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1-s2.0-S2666379120301816-main.pdf | Published version | 3.62 MB | Adobe PDF | View/Open |
Title: | A high content screen for mucin-1-reducing compounds identifies fostamatinib as a candidate for rapid repurposing for acute lung injury |
Authors: | Kost-Alimova, M Sidhom, E-H Satyam, A Chamberlain, BT Dvela-Levitt, M Melanson, M Alper, SL Santos, J Gutierrez, J Subramanian, A Byrne, PJ Grinkevich, E Bricio, ER Kim, C Clark, A Watts, A Thompson, R Marshall, J Pablo, JL Coraor, J Roignot, J Vernon, KA Keller, K Campbell, A Emani, M Racette, M Bazua-Valenti, S Padovano, V Weins, A McAdoo, SP Tam, FWK Ronco, L Wagner, F Tsokos, GC Shaw, JL Greka, A |
Item Type: | Journal Article |
Abstract: | Drug repurposing has the advantage of identifying potential treatments on a shortened timescale. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high-content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce mucin-1 (MUC1) protein abundance. Elevated MUC1 levels predict the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and correlate with poor clinical outcomes. Our screen identifies fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, fostamatinib reduces MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by the active metabolite R406 promotes MUC1 removal from the cell surface. Our work suggests fostamatinib as a repurposing drug candidate for ALI. |
Issue Date: | 17-Nov-2020 |
Date of Acceptance: | 13-Oct-2020 |
URI: | http://hdl.handle.net/10044/1/83980 |
DOI: | 10.1016/j.xcrm.2020.100137 |
ISSN: | 2666-3791 |
Publisher: | Elsevier BV |
Start Page: | 1 |
End Page: | 15 |
Journal / Book Title: | Cell Reports Medicine |
Volume: | 1 |
Issue: | 8 |
Copyright Statement: | © 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
Keywords: | ALI ARDS COVID-19 MUC1 SARS-CoV-2 acute lung injury acute respiratory distress syndrome drug repurposing fostamatinib |
Publication Status: | Published |
Article Number: | 100137 |
Online Publication Date: | 2020-10-29 |
Appears in Collections: | Department of Immunology and Inflammation Faculty of Medicine |
This item is licensed under a Creative Commons License