Wang Zhisong, Gao Yan, He Lei, Sun Shuhao, Xia Tingting, Hu Lu, Yao Licheng, Wang Liangliang, Li Dan, Shi Hui, Liao Xuebin
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, Beijing 100084, China.
Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, Beijing 100084, China.
J Med Chem. 2021 Jun 10;64(11):7507-7532. doi: 10.1021/acs.jmedchem.1c00179. Epub 2021 May 28.
Activation of the toll-like receptors 7 and 8 has emerged as a promising strategy for cancer immunotherapy. Herein, we report the design and synthesis of a series of pyrido[3,2-]pyrimidine-based toll-like receptor 7/8 dual agonists that exhibited potent and near-equivalent agonistic activities toward TLR7 and TLR8. In vitro, compounds and significantly induced the secretion of IFN-α, IFN-γ, TNF-α, IL-1β, IL-12p40, and IP-10 in human peripheral blood mononuclear cell assays. In vivo, compounds , , and significantly suppressed tumor growth in CT26 tumor-bearing mice by remodeling the tumor microenvironment. Additionally, compounds , , and markedly improved the antitumor activity of PD-1/PD-L1 blockade. In particular, compound combined with the anti-PD-L1 antibody led to complete tumor regression. These results demonstrated that TLR7/8 agonists (, , and ) held great potential as single agents or in combination with PD-1/PD-L1 blockade for cancer immunotherapy.
Toll样受体7和8的激活已成为一种很有前景的癌症免疫治疗策略。在此，我们报告了一系列基于吡啶并[3,2-]嘧啶的Toll样受体7/8双重激动剂的设计与合成，这些激动剂对TLR7和TLR8表现出强效且近乎等效的激动活性。在体外，化合物 和 在人外周血单核细胞试验中显著诱导了IFN-α、IFN-γ、TNF-α、IL-1β、IL-12p40和IP-10的分泌。在体内，化合物 、 和 通过重塑肿瘤微环境显著抑制了CT26荷瘤小鼠的肿瘤生长。此外，化合物 、 和 显著提高了PD-1/PD-L1阻断的抗肿瘤活性。特别是，化合物 与抗PD-L1抗体联合导致肿瘤完全消退。这些结果表明，TLR7/8激动剂（ 、 和 ）作为单一药物或与PD-1/PD-L1阻断联合用于癌症免疫治疗具有巨大潜力。
