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 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; Luciene Ronco; Florence Wagner; George C. Tsokos; Jillian L. Shaw; Anna Greka

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

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 journal › Article › peer-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 language	English
Article number	100137
Journal	Cell Reports Medicine
Volume	1
Issue number	8
DOIs	https://doi.org/10.1016/j.xcrm.2020.100137
State	Published - 17 Nov 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2020 The Author(s)

Funding

We gratefully acknowledge stimulating discussions with Broad Institute colleagues Deborah Hung, Ramnik Xavier, Jay Rajagopal, and Aviv Regev. We thank Terry Woo (BWH Pathology) and Stephen Straub (Perkin-Elmer) for excellent technical support and expertise. SYK inhibitor R788 was provided as a gift to G.C.T. by Rigel Pharmaceuticals. This work was supported by PHS NIH R01AI148161 (to G.C.T.) and by the Slim Initiative for Genomic Medicine in the Americas (SIGMA), a collaboration of the Broad Institute with the Carlos Slim Foundation. F.W.K.T. is supported by the Ken and Mary Minton Chair of Renal Medicine . F.W.K.T. has received research project grants from 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.

Funders	Funder number
PHS NIH	R01AI148161
Rigel Pharmaceuticals
Broad Institute
Instituto Carlos Slim de la Salud	NCT02112838

Keywords

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

Access to Document

10.1016/j.xcrm.2020.100137

Cite this

Kost-Alimova, M., Sidhom, E. H., Satyam, A., Chamberlain, B. T., Dvela-Levitt, M., Melanson, M., Alper, S. L., Santos, J., Gutierrez, J., Subramanian, A., Byrne, P. J., Grinkevich, E., Reyes-Bricio, E., Kim, C., Clark, A. R., Watts, A. J. B., Thompson, R., Marshall, J., Pablo, J. L., ... Greka, A. (2020). A High-Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury. Cell Reports Medicine, 1(8), Article 100137. https://doi.org/10.1016/j.xcrm.2020.100137

@article{86bef16cd252419db5a1a29e84c1ea24,

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

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.",

keywords = "ALI, ARDS, COVID-19, MUC1, SARS-CoV-2, acute lung injury, acute respiratory distress syndrome, drug repurposing, fostamatinib",

author = "Maria Kost-Alimova and Sidhom, {Eriene Heidi} and Abhigyan Satyam and Chamberlain, {Brian T.} and Moran Dvela-Levitt and Michelle Melanson and Alper, {Seth L.} and Jean Santos and Juan Gutierrez and Ayshwarya Subramanian and Byrne, {Patrick J.} and Elizabeth Grinkevich and Estefan{\'i}a Reyes-Bricio and Choah Kim and Clark, {Abbe R.} and Watts, {Andrew J.B.} and Rebecca Thompson and Jamie Marshall and Pablo, {Juan Lorenzo} and Juliana Coraor and Julie Roignot and Vernon, {Katherine A.} and Keith Keller and Alissa Campbell and Maheswarareddy Emani and Matthew Racette and Silvana Bazua-Valenti and Valeria Padovano and Astrid Weins and McAdoo, {Stephen P.} and Tam, {Frederick W.K.} and Luciene Ronco and Florence Wagner and Tsokos, {George C.} and Shaw, {Jillian L.} and Anna Greka",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = nov,

day = "17",

doi = "10.1016/j.xcrm.2020.100137",

language = "אנגלית",

volume = "1",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "8",

}

Kost-Alimova, M, Sidhom, EH, 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, JL, 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 2020, 'A High-Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury', Cell Reports Medicine, vol. 1, no. 8, 100137. https://doi.org/10.1016/j.xcrm.2020.100137

TY - JOUR

T1 - A High-Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury

AU - Kost-Alimova, Maria

AU - Sidhom, Eriene Heidi

AU - Satyam, Abhigyan

AU - Chamberlain, Brian T.

AU - Dvela-Levitt, Moran

AU - Melanson, Michelle

AU - Alper, Seth L.

AU - Santos, Jean

AU - Gutierrez, Juan

AU - Subramanian, Ayshwarya

AU - Byrne, Patrick J.

AU - Grinkevich, Elizabeth

AU - Reyes-Bricio, Estefanía

AU - Kim, Choah

AU - Clark, Abbe R.

AU - Watts, Andrew J.B.

AU - Thompson, Rebecca

AU - Marshall, Jamie

AU - Pablo, Juan Lorenzo

AU - Coraor, Juliana

AU - Roignot, Julie

AU - Vernon, Katherine A.

AU - Keller, Keith

AU - Campbell, Alissa

AU - Emani, Maheswarareddy

AU - Racette, Matthew

AU - Bazua-Valenti, Silvana

AU - Padovano, Valeria

AU - Weins, Astrid

AU - McAdoo, Stephen P.

AU - Tam, Frederick W.K.

AU - Ronco, Luciene

AU - Wagner, Florence

AU - Tsokos, George C.

AU - Shaw, Jillian L.

AU - Greka, Anna

PY - 2020/11/17

Y1 - 2020/11/17

N2 - 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.

AB - 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.

KW - ALI

KW - ARDS

KW - COVID-19

KW - MUC1

KW - SARS-CoV-2

KW - acute lung injury

KW - acute respiratory distress syndrome

KW - drug repurposing

KW - fostamatinib

UR - http://www.scopus.com/inward/record.url?scp=85096610281&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2020.100137

DO - 10.1016/j.xcrm.2020.100137

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 33294858

AN - SCOPUS:85096610281

SN - 2666-3791

VL - 1

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 8

M1 - 100137

ER -

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

Abstract

Bibliographical note

Funding

Keywords

Access to Document

Other files and links

Fingerprint

Cite this