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- W3120676265 abstract "Leukocyte inflammatory responses require integrin cell-adhesion molecule signaling through spleen tyrosine kinase (Syk), a non-receptor kinase that binds directly to integrin β-chain cytoplasmic domains. Here, we developed a high-throughput screen to identify small molecule inhibitors of the Syk-integrin cytoplasmic domain interactions. Screening small molecule compound libraries identified the β-lactam antibiotics cefsulodin and ceftazidime, which inhibited integrin β-subunit cytoplasmic domain binding to the tandem SH2 domains of Syk (IC50 range, 1.02-4.9 µM). Modeling suggested antagonist binding to Syk outside the pITAM binding site. Ceftazidime inhibited integrin signaling via Syk, including inhibition of adhesion-dependent upregulation of interleukin-1β and monocyte chemoattractant protein-1, but did not inhibit ITAM-dependent phosphorylation of Syk mediated by FcγRI signaling. Our results demonstrate a novel means to target Syk independent of its kinase and pITAM binding sites such that integrin signaling via this kinase is abrogated but ITAM-dependent signaling remains intact. As integrin signaling through Syk is essential for leukocyte activation, this may represent a novel approach to target inflammation." @default.
- W3120676265 created "2021-01-18" @default.
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- W3120676265 date "2021-01-08" @default.
- W3120676265 modified "2023-09-29" @default.
- W3120676265 title "Identification of Inhibitors of Integrin Cytoplasmic Domain Interactions With Syk" @default.
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- W3120676265 doi "https://doi.org/10.3389/fimmu.2020.575085" @default.
- W3120676265 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7819857" @default.
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- W3120676265 hasPublicationYear "2021" @default.
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