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

Maria Kost-Alimova, Eriene Heidi Sidhom, Abhigyan Satyam, Brian T. Chamberlain, Moran Dvela-Levitt, Michelle Melanson, Seth L. Alper, Jean Santos, Juan Gutierrez, Ayshwarya Subramanian, Patrick J. Byrne, Elizabeth Grinkevich, Estefanía Reyes-Bricio, Choah Kim, Abbe R. Clark, Andrew J.B. Watts, Rebecca Thompson, Jamie Marshall, Juan Lorenzo Pablo, Juliana CoraorJulie Roignot, Katherine A. Vernon, Keith Keller, Alissa Campbell, Maheswarareddy Emani, Matthew Racette, Silvana Bazua-Valenti, Valeria Padovano, Astrid Weins, Stephen P. McAdoo, Frederick W.K. Tam, Luciene Ronco, Florence Wagner, George C. Tsokos, Jillian L. Shaw, Anna Greka

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish
Article number100137
JournalCell Reports Medicine
Volume1
Issue number8
DOIs
StatePublished - 17 Nov 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 The Author(s)

Keywords

  • ALI
  • ARDS
  • COVID-19
  • MUC1
  • SARS-CoV-2
  • acute lung injury
  • acute respiratory distress syndrome
  • drug repurposing
  • fostamatinib

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