AUTHOR=Bakthavatsalam Deenadayalan , Craft John W. , Kazansky Anna , Nguyen Nghi , Bae Goeun , Caivano Amy R. , Gundlach C. William , Aslam Asra , Ali Safa , Gupta Shashikant , Lin Sophie Y. , Parthiban Hema D. , Vanderslice Peter , Stephan Clifford C. , Woodside Darren G. 

TITLE=Identification of Inhibitors of Integrin Cytoplasmic Domain Interactions With Syk

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.575085

DOI=10.3389/fimmu.2020.575085

ISSN=1664-3224

ABSTRACT=<p>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 (IC<sub>50</sub> range, 1.02–4.9 µM). Modeling suggested antagonist binding to Syk outside the pITAM binding site. Ceftazidime inhibited integrin signaling <italic>via</italic> 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 <italic>via</italic> 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.</p>