化学
前药
免疫抑制
细胞质
体内
免疫系统
免疫疗法
癌症研究
癌症免疫疗法
药理学
生物化学
免疫学
生物
生物技术
作者
Renming Fan,Aohua Deng,Bing Qi,Shuo Zhang,Ruoxi Sang,Lanxin Luo,Jiakui Gou,Yongqing Liu,Ruizhuo Lin,Ming Zhao,Yang Liu,Le Yang,Maosheng Cheng,Gaofei Wei,Maosheng Cheng,Gaofei Wei
标识
DOI:10.1021/acs.jmedchem.2c01719
摘要
Platinum drugs as primary chemotherapy drugs have been applied to various cancer patients. However, their therapeutic applicability is limited due to the adverse effects and immunosuppression. To minimize the side effects and boost the immune response, we designed and synthesized platinum(IV) prodrugs that introduced BRD4 inhibitor JQ-1. Among them, CJ2 had the most potent therapeutic activity and less toxicity. With the introduction of ligand JQ-1, CJ2-reduced PD-L1 protein was found in the cytoplasm and cytomembrane for the first time. By interfering with the PD-L1 synthesis, CJ2 could arouse the immune system and promote CD8+ T cell infiltration. Meanwhile, CJ2 could accelerate PD-L1 degradation in the cytoplasm to block DNA damage repair. In vivo, CJ2 markedly suppressed tumor growth by reversing the immunosuppression microenvironment and enhancing DNA damage. These findings provide an effective approach to improve the selectivity and activity of the platinum drugs with elevated immune response.
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