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
The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Cell Rep Med. 2020 Oct 29;1(8):100137. doi: 10.1016/j.xcrm.2020.100137. eCollection 2020 Nov 17.
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. , fostamatinib reduces MUC1 abundance in lung epithelial cells in a mouse model of ALI. , 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.
药物重新利用具有在较短时间内确定潜在治疗方法的优势。针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的大流行传播，我们利用了对处于临床开发不同阶段的3713种化合物进行的高内涵筛选，以确定可降低粘蛋白-1（MUC1）蛋白丰度的美国食品药品监督管理局（FDA）批准的化合物。MUC1水平升高预示着急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的发展，并与不良临床结果相关。我们的筛选确定了 fostamatinib（R788），一种已被批准用于治疗慢性免疫性血小板减少症的脾酪氨酸激酶（SYK）抑制剂，作为治疗ALI的重新利用候选药物。在ALI小鼠模型中，fostamatinib可降低肺上皮细胞中MUC1的丰度。活性代谢物R406对SYK的抑制作用促进了MUC1从细胞表面的清除。我们的研究表明fostamatinib是一种用于ALI的重新利用药物候选物。
