化学
微尺度热泳
外周血单个核细胞
体内
小分子
细胞毒性
癌症免疫疗法
对接(动物)
免疫系统
免疫疗法
癌症研究
药理学
生物化学
体外
免疫学
生物
生物技术
护理部
医学
作者
Chengliang Sun,Yuling He,Gefei Wang,Guoyu Zhang,Yu Zhang,Hao Shen,Lingrong Hu,Yanze Sun,Binjian Jiang,Xiao Wang,Kai Yuan,Wenjian Min,Li Wang,Haopeng Sun,Yibei Xiao,Peng Yang
标识
DOI:10.1021/acs.jmedchem.3c02039
摘要
VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidine-based VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KD value of 0.49 ± 0.20 μM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.
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