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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 during the COVID-19 pandemic

Maria Alimova, Eriene-Heidi Sidhom, Abhigyan Satyam, Moran Dvela-Levitt, Michelle Melanson, Brian T. Chamberlain, Seth L. Alper, Jean Santos, Juan Gutierrez, Ayshwarya Subramanian, Elizabeth Grinkevich, Estefania Reyes Bricio, Choah Kim, Abbe Clark, Andrew Watts, Rebecca Thompson, Jamie Marshall, Juan Lorenzo Pablo, Juliana Coraor, Julie 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, Lucienne Ronco, Florence Wagner, George C. Tsokos, View ORCID ProfileJillian L. Shaw, View ORCID ProfileAnna Greka
doi: https://doi.org/10.1101/2020.06.30.180380
Maria Alimova
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Eriene-Heidi Sidhom
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Abhigyan Satyam
3Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
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Moran Dvela-Levitt
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Michelle Melanson
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Brian T. Chamberlain
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Seth L. Alper
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
3Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
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Jean Santos
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Juan Gutierrez
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Ayshwarya Subramanian
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Elizabeth Grinkevich
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Estefania Reyes Bricio
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Choah Kim
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Abbe Clark
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Andrew Watts
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Rebecca Thompson
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Jamie Marshall
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Juan Lorenzo Pablo
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Juliana Coraor
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Julie Roignot
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Katherine A. Vernon
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Keith Keller
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Alissa Campbell
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Maheswarareddy Emani
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Matthew Racette
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Silvana Bazua-Valenti
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Valeria Padovano
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Astrid Weins
2Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Stephen P. McAdoo
4Department of Immunology and Inflammation, Imperial College, Hammersmith Hospital, London, UK
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Frederick W.K. Tam
4Department of Immunology and Inflammation, Imperial College, Hammersmith Hospital, London, UK
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Lucienne Ronco
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Florence Wagner
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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George C. Tsokos
3Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
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Jillian L. Shaw
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Anna Greka
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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  • ORCID record for Anna Greka
  • For correspondence: agreka@bwh.harvard.edu
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Summary

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 Statement

Declaration 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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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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 during the COVID-19 pandemic
Maria Alimova, Eriene-Heidi Sidhom, Abhigyan Satyam, Moran Dvela-Levitt, Michelle Melanson, Brian T. Chamberlain, Seth L. Alper, Jean Santos, Juan Gutierrez, Ayshwarya Subramanian, Elizabeth Grinkevich, Estefania Reyes Bricio, Choah Kim, Abbe Clark, Andrew Watts, Rebecca Thompson, Jamie Marshall, Juan Lorenzo Pablo, Juliana Coraor, Julie 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, Lucienne Ronco, Florence Wagner, George C. Tsokos, Jillian L. Shaw, Anna Greka
bioRxiv 2020.06.30.180380; doi: https://doi.org/10.1101/2020.06.30.180380
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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 during the COVID-19 pandemic
Maria Alimova, Eriene-Heidi Sidhom, Abhigyan Satyam, Moran Dvela-Levitt, Michelle Melanson, Brian T. Chamberlain, Seth L. Alper, Jean Santos, Juan Gutierrez, Ayshwarya Subramanian, Elizabeth Grinkevich, Estefania Reyes Bricio, Choah Kim, Abbe Clark, Andrew Watts, Rebecca Thompson, Jamie Marshall, Juan Lorenzo Pablo, Juliana Coraor, Julie 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, Lucienne Ronco, Florence Wagner, George C. Tsokos, Jillian L. Shaw, Anna Greka
bioRxiv 2020.06.30.180380; doi: https://doi.org/10.1101/2020.06.30.180380

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