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Cell Rep Med DOI:10.1016/j.xcrm.2020.100137

A High-Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury.

Publication TypeJournal Article
Year of Publication2020
AuthorsKost-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, Reyes-Bricio, E, Kim, C, Clark, AR, Watts, AJB, Thompson, R, Marshall, J, Pablo, JLorenzo, 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
JournalCell Rep Med
Volume1
Issue8
Pages100137
Date Published2020 Nov 17
ISSN2666-3791
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. , fostamatinib reduces MUC1 abundance in lung epithelial cells in a mouse model of ALI. , 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.

DOI10.1016/j.xcrm.2020.100137
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/33294858?dopt=Abstract

Alternate JournalCell Rep Med
PubMed ID33294858
PubMed Central IDPMC7691435
Grant ListR01 AI042269 / AI / NIAID NIH HHS / United States
R01 AI148161 / AI / NIAID NIH HHS / United States
T32 HL007627 / HL / NHLBI NIH HHS / United States