Heterocyclic-Modified Imidazoquinoline Derivatives: Selective TLR7 Agonist Regulates Tumor Microenvironment against Melanoma
Jiaxin Ou, Lu Zheng, Yanlin Chen, Qiuyue Fu, Liyi Tan, En Liang, Lan Huang, Yue Pan, Jiahua Ke, Zhipeng Chen, Kui Cheng
Abstract
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 (EC 50 = 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.