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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.
Kost-Alimova, Maria; Sidhom, Eriene-Heidi; Satyam, Abhigyan; Chamberlain, Brian T; Dvela-Levitt, Moran; Melanson, Michelle; Alper, Seth L; Santos, Jean; Gutierrez, Juan; Subramanian, Ayshwarya; Byrne, Patrick J; Grinkevich, Elizabeth; Reyes-Bricio, Estefanía; Kim, Choah; Clark, Abbe R; Watts, Andrew J B; Thompson, Rebecca; Marshall, Jamie; Pablo, Juan Lorenzo; Coraor, Juliana; Roignot, Julie; Vernon, Katherine A; Keller, Keith; Campbell, Alissa; Emani, Maheswarareddy; Racette, Matthew; Bazua-Valenti, Silvana; Padovano, Valeria; Weins, Astrid; McAdoo, Stephen P; Tam, Frederick W K; Ronco, Luciene; Wagner, Florence; Tsokos, George C; Shaw, Jillian L; Greka, Anna.
  • Kost-Alimova M; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Sidhom EH; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Satyam A; Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Chamberlain BT; Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • Dvela-Levitt M; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Melanson M; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Alper SL; Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Santos J; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gutierrez J; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Subramanian A; Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • Byrne PJ; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Grinkevich E; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Reyes-Bricio E; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Kim C; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Clark AR; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Watts AJB; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Thompson R; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Marshall J; Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Pablo JL; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Coraor J; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Roignot J; Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Vernon KA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Keller K; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Campbell A; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Emani M; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Racette M; Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Bazua-Valenti S; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Padovano V; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Weins A; Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • McAdoo SP; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Tam FWK; Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Ronco L; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wagner F; Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Tsokos GC; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Shaw JL; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Greka A; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cell Rep Med ; 1(8): 100137, 2020 11 17.
Article in English | MEDLINE | ID: covidwho-1386734
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.
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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Journal: Cell Rep Med Year: 2020 Document Type: Article Affiliation country: J.XCRM.2020.100137

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Journal: Cell Rep Med Year: 2020 Document Type: Article Affiliation country: J.XCRM.2020.100137