Structure-Based Design of Highly Potent Toll-like Receptor 7/8 Dual Agonists for Cancer Immunotherapy
Zhisong Wang, Yan Gao, Lei He, Shuhao Sun, Tingting Xia, Lu Hu, Licheng Yao, Liangliang Wang, Dan Li, Hui Shi, Xuebin Liao
Abstract
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-d]pyrimidine-based toll-like receptor 7/8 dual agonists that exhibited potent and near-equivalent agonistic activities toward TLR7 and TLR8. In vitro, compounds 24e and 25a 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 24e, 24m, and 25a significantly suppressed tumor growth in CT26 tumor-bearing mice by remodeling the tumor microenvironment. Additionally, compounds 24e, 24m, and 25a markedly improved the antitumor activity of PD-1/PD-L1 blockade. In particular, compound 24e combined with the anti-PD-L1 antibody led to complete tumor regression. These results demonstrated that TLR7/8 agonists (24e, 24m, and 25a) held great potential as single agents or in combination with PD-1/PD-L1 blockade for cancer immunotherapy.