Structure-Based Design of Highly Potent Toll-like Receptor 7/8 Dual Agonists for Cancer Immunotherapy

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.