主要组织相容性复合体
小分子
滞后
功能(生物学)
MHC I级
基因
计算生物学
癌症免疫疗法
细胞毒性T细胞
免疫疗法
癌症研究
计算机科学
细胞生物学
生物
免疫学
体外
生物化学
免疫系统
计算机网络
作者
Somaya A. Abdel‐Rahman,Ashfaq Ur Rehman,Moustafa T. Gabr
标识
DOI:10.1021/acsmedchemlett.3c00054
摘要
Lymphocyte activation gene 3 (LAG-3) is a negative immune checkpoint that plays a key role in downregulating the immune response to cancer. Inhibition of LAG-3 interactions allows T cells to regain cytotoxic activity and reduce the immunosuppressive function of regulating T cells. We utilized a combination approach of focused screening and “SAR by catalog” to identify small molecules that function as dual inhibitors of the interactions of LAG-3 with major histocompatibility complex (MHC) class II and fibrinogen-like protein 1 (FGL1). Our top hit compound inhibited both LAG-3/MHCII and LAG-3/FGL1 interactions in biochemical binding assays with IC50 values of 4.21 ± 0.84 and 6.52 ± 0.47 μM, respectively. Moreover, we have demonstrated the ability of our top hit compound to block LAG-3 interactions in cell-based assays. This work will pave the way for future drug discovery efforts aiming at the development of LAG-3-based small molecules for cancer immunotherapy.
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