PT  - JOURNAL ARTICLE
AU  - Maria Alimova
AU  - Eriene-Heidi Sidhom
AU  - Abhigyan Satyam
AU  - Moran Dvela-Levitt
AU  - Michelle Melanson
AU  - Brian T. Chamberlain
AU  - Seth L. Alper
AU  - Jean Santos
AU  - Juan Gutierrez
AU  - Ayshwarya Subramanian
AU  - Elizabeth Grinkevich
AU  - Estefania Reyes Bricio
AU  - Choah Kim
AU  - Abbe Clark
AU  - Andrew Watts
AU  - Rebecca Thompson
AU  - Jamie Marshall
AU  - Juan Lorenzo Pablo
AU  - Juliana Coraor
AU  - Julie Roignot
AU  - Katherine A. Vernon
AU  - Keith Keller
AU  - Alissa Campbell
AU  - Maheswarareddy Emani
AU  - Matthew Racette
AU  - Silvana Bazua-Valenti
AU  - Valeria Padovano
AU  - Astrid Weins
AU  - Stephen P. McAdoo
AU  - Frederick W.K. Tam
AU  - Lucienne Ronco
AU  - Florence Wagner
AU  - George C. Tsokos
AU  - Jillian L. Shaw
AU  - Anna Greka
TI  - A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic
AID  - 10.1101/2020.06.30.180380
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.30.180380
4099  - http://biorxiv.org/content/early/2020/06/30/2020.06.30.180380.short
4100  - http://biorxiv.org/content/early/2020/06/30/2020.06.30.180380.full
AB  - Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. 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 MUC1 protein abundance. Our screen identified 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 reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.Competing Interest StatementDeclaration of Interests The authors declare no competing interests. FWKT has received research project grants from Rigel Pharmaceuticals, and has consultancy agreements with Rigel Pharmaceuticals, and is the Chief Investigator of an international clinical trial of a SYK inhibitor in IgA nephropathy (ClinicalTrials.gov NCT02112838), funded by Rigel Pharmaceuticals.