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.
A 286982是一种有效的白细胞相关功能抗原-1/细胞内黏附分子-1（LFA-1/ICAM-1）相互作用的非肽抑制剂，在LFA-1/ICAM-1结合试验和LFA-1介导的细胞粘附试验中，其IC50值分别为44和35nM[1]。LFA-1与ICAM-1的相互作用对于免疫细胞向抗原呈递细胞的黏附和募集以及NK细胞的细胞杀伤至关重要[2]。
体外实验中，以22-176nM的A 286982处理49h，可剂量依赖性降低干扰素刺激基因5（ISG15）刺激的NK-92细胞分泌IFN-γ的能力[2]。以88nM A 286982处理24-48h，可抑制巨噬细胞分泌CC趋化因子配体18（CCL18），并阻断ISG15诱导的Src原癌基因酪氨酸蛋白激酶（SRC）信号通路的激活[3]。以100nM A 286982处理12-24h，可显著降低与A549细胞共培养的外周血单核细胞（PBMC）分离的CD8⁺T细胞中细胞毒性标志物GZMB和活化标志物CD69的表达[4]。