A 286982 is a potent, nonpeptide inhibitors of leukocyte function-associated antigen-1/ intracellular adhesion molecule-1 (LFA-1/ICAM-1) interaction, with IC50 values of 44 and 35nM in LFA-1/ICAM-1 binding assay and LFA-1-mediated cellular adhesion assay, respectively[1]. The interaction of LFA-1 with ICAM-1 is critical for adhesion and recruitment of immune cells to antigen-presenting cells and for cell killing by NK cells[2].
In vitro, treatment with A-286982 at 22–176nM for 49h dose-dependently reduced Interferon-Stimulated Gene 15 (ISG15)-induced IFN-γ secretion in NK-92 cells[2]. Treatment with 88nM A 286982 for 24-48h inhibited C-C motif chemokine ligand 18 (CCL18) secretion in macrophages and blocked ISG15-induced activation of the Proto-oncogene tyrosine-protein kinase Src (SRC) signaling pathway[3]. Treatment with 100nM A 286982 for 12-24h significantly reduced the expression of the cytotoxic marker GZMB and the activation marker CD69 in CD8⁺T cells isolated from peripheral blood mononuclear cells (PBMCs) co-cultured with A549 cells[4].
References:
[1] Liu G, Link JT, Pei Z, et al. Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 1. Identification of an additional binding pocket based on an anilino diaryl sulfide lead. J Med Chem. 2000;43(21):4025-4040.
[2] Swaim CD, Scott AF, Canadeo LA, Huibregtse JM. Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor. Mol Cell. 2017;68(3):581-590.e5.
[3] Chen RH, Xiao ZW, Yan XQ, et al. Tumor Cell-Secreted ISG15 Promotes Tumor Cell Migration and Immune Suppression by Inducing the Macrophage M2-Like Phenotype. Front Immunol. 2020;11:594775.
[4] Wang CL, Ho AS, Chang CC, et al. Radiotherapy enhances CXCR3highCD8+ T cell activation through inducing IFNγ-mediated CXCL10 and ICAM-1 expression in lung cancer cells. Cancer Immunol Immunother. 2023;72(6):1865-1880.