Heterocyclic-Modified Imidazoquinoline Derivatives: Selective TLR7 Agonist Regulates Tumor Microenvironment against Melanoma.
Heterocyclic-Modified Imidazoquinoline Derivatives: Selective TLR7 Agonist Regulates Tumor Microenvironment against Melanoma.
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DOI：
10.1021/acs.jmedchem.3c01504
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发表时间：
2024-02
影响因子：
7.3
通讯作者：
Jiaxin Ou;Lu Zheng;Yanlin Chen;Qiuyue Fu;Liyi Tan;En Liang;Lan Huang;Yue Pan;Jiahua Ke;Zhipeng Chen;Kui Cheng
中科院分区：
文献类型：
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作者：
Jiaxin Ou;Lu Zheng;Yanlin Chen;Qiuyue Fu;Liyi Tan;En Liang;Lan Huang;Yue Pan;Jiahua Ke;Zhipeng Chen;Kui Cheng
针对 Toll 样受体 7 (TLR7) 的免疫疗法是一种有前景的癌症治疗策略。在此，我们描述了一系列基于咪唑喹啉的 TLR7 激动剂的设计和合成，并使用 HEK-Blue hTLR7 细胞评估 NF-κB 通路激活，以确定最有效的小分子 TLR7 激动剂 SMU-L11 (EC50 = 0.024 ± 0.002 μM)。体外实验表明，SMU-L11 特异性激活 TLR7，从而招募 MyD88 接头蛋白并激活 NF-κB 和 MAPK 信号通路。此外，SMU-L11被发现通过显着诱导小鼠树突状细胞、巨噬细胞和人外周血单核细胞分泌促炎细胞因子，同时促进M1巨噬细胞极化来发挥免疫增强作用。使用 B16-F10 小鼠肿瘤模型的体内研究表明，SMU-L11 显着增强免疫细胞活化并增强 CD4+ T 和 CD8+ T 细胞增殖，直接杀死肿瘤细胞并抑制肿瘤生长。
Immunotherapy targeting the toll-like receptor 7 (TLR7) is a promising strategy for cancer treatment. Herein, we describe the design and synthesis of a series of imidazoquinoline-based TLR7 agonists and assess NF-κB pathway activation using HEK-Blue hTLR7 cells to identify the most potent small-molecule TLR7 agonist, SMU-L11 (EC50 = 0.024 ± 0.002 μM). In vitro experiments demonstrated that SMU-L11 specifically activated TLR7, resulting in recruitment of the MyD88 adaptor protein and activation of the NF-κB and MAPK signaling pathways. Moreover, SMU-L11 was found to exert immune-enhancing effects by significantly inducing the secretion of proinflammatory cytokines in murine dendritic cells, macrophages, and human peripheral blood mononuclear cells while promoting M1 macrophage polarization. In vivo studies using a B16-F10 mouse tumor model showed that SMU-L11 significantly enhanced immune cell activation and augmented CD4+ T and CD8+ T-cell proliferation, directly killing tumor cells and inhibiting tumor growth.