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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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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



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