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/articles/10.3389/fimmu.2020.575085 DOI=10.3389/fimmu.2020.575085 ISSN=1664-3224 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.