Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents.
Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents.
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调节 PD-1/PD-L1 相互作用的新型邻苯二甲酰亚胺作为潜在的免疫治疗药物
DOI：
10.1016/j.apsb.2022.04.007
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发表时间：
2022-12
影响因子：
14.5
通讯作者：
Yang, Peng
中科院分区：
文献类型：
--
作者：
Sun, Chengliang;Cheng, Yao;Liu, Xiaojia;Wang, Gefei;Min, Wenjian;Wang, Xiao;Yuan, Kai;Hou, Yi;Li, Jiaxing;Zhang, Haolin;Dong, Haojie;Wang, Liping;Lou, Chenguang;Sun, Yanze;Yu, Xinmiao;Deng, Hongbin;Xiao, Yibei;Yang, Peng
程序性细胞死亡1(PD-1)/程序性细胞死亡配体1（PD-L1）已成为癌症免疫治疗中最有前途的免疫检查点靶点之一。尽管小分子抑制剂比抗体具有固有的优势，但小分子抑制剂的发现却落后于抗体药物。基于对小分子抑制剂与PD-L1蛋白对接的研究，将抑制剂的化学连接体由柔性链变为芳香环可能会提高其与PD-L1蛋白的结合能力，这在之前的报道中没有报道。通过结构合理设计，合成了一系列新型邻苯二甲酸亚胺衍生物。P39不仅能抑制PD-1/PD-L1相互作用（IC50 = 8.9 nmol/L），还能增强免疫细胞对肿瘤细胞的杀伤作用，是具有良好活性的最佳抑制剂。共晶数据表明，P39诱导PD-L1蛋白二聚化，从而阻断PD-1/PD-L1的结合。此外，P39在LD50 ~ 5000 mg/kg范围内表现出良好的安全性，并通过促进CD8+ T细胞活化显示出显著的体内抗肿瘤活性。这些数据表明，P39作为一种有前景的小化学抑制剂作用于PD-1/PD-L1轴，具有提高t细胞免疫治疗效果的潜力。邻苯二胺衍生物P39诱导PD-L1蛋白二聚化，从而阻断PD-1/PD-L1的结合，抑制肿瘤细胞的免疫逃逸。
Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind that of antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein, which was not reported before. A series of novel phthalimide derivatives from structure-based rational design was synthesized. P39 was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC50 = 8.9 nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, P39 exhibited a favorable safety profile with a LD50 > 5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8+ T cell activation. All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells. Phthalimide derivative P39 induced dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1 and inhibiting immune escape of tumor cells.
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DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
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作者：
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通讯作者：
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DOI：
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发表时间：
2006-01-01
影响因子：
2.2
作者：
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通讯作者：
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影响因子：
7.3
作者：
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通讯作者：
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小檗碱通过抑制 CSN5 的去泛素化活性减少癌细胞 PD-L1 表达并促进抗肿瘤免疫
DOI：
10.1016/j.apsb.2020.06.014
发表时间：
2020-12
期刊：
Acta pharmaceutica Sinica. B
影响因子：
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作者：
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通讯作者：
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DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
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作者：
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通讯作者：
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