癌症免疫疗法
免疫疗法
肿瘤微环境
免疫系统
T细胞
癌症
免疫检查点
CD8型
小分子
癌细胞
癌症研究
化学
生物
免疫学
生物化学
遗传学
作者
Menghan Wu,Aijun Wu,Xiangrui Zhang,Yang Li,Beibei Li,Shengzhe Jin,Qingyu Dong,Xiaoshuang Niu,Lihan Zhang,Xiaowen Zhou,Jiangfeng Du,WU Yi-ming,Wenjie Zhai,Xiaoxi Zhou,Lu Qiu,Yanfeng Gao,Weihua Zhao
标识
DOI:10.1016/j.bcp.2023.115583
摘要
PD-1/PD-L1 blockade has achieved substantial clinical results in cancer treatment. However, the expression of other immune checkpoints leads to resistance and hinders the efficacy of PD-1/PD-L1 blockade. T cell immunoglobulin and mucin domain 3 (TIM-3), a non-redundant immune checkpoint, synergizes with PD-1 to mediate T cell dysfunction in tumor microenvironment. Development of small molecules targeting TIM-3 is a promising strategy for cancer immunotherapy. Here, to identify small molecule inhibitors targeting TIM-3, the docking pocket in TIM-3 was analyzed by Molecular Operating Environment (MOE) and the Chemdiv compound database was screened. The small molecule SMI402 could bind to TIM-3 with high affinity and prevent the ligation of PtdSer, HMGB1, and CEACAM1. SMI402 reinvigorated T cell function in vitro. In the MC38-bearing mouse model, SMI402 inhibited tumor growth by increasing CD8+ T and natural killing (NK) cells infiltration at the tumor site, as well as restoring the function of CD8+ T and NK cells. In conclusions, the small molecule SMI402 shows promise as a leading compound which targets TIM-3 for cancer immunotherapy.
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