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

Area of Science:

• Immunology
• Medicinal Chemistry
• Oncology

Background:

• Activation of toll-like receptors 7 and 8 (TLR7/8) is a promising cancer immunotherapy strategy.
• Developing potent and selective TLR7/8 agonists is crucial for therapeutic advancement.

Purpose of the Study:

• To design and synthesize novel pyrido[3,2-d]pyrimidine-based compounds as dual TLR7/8 agonists.
• To evaluate the in vitro and in vivo efficacy of these compounds in cancer models.

Main Methods:

• Synthesis of pyrido[3,2-d]pyrimidine derivatives.
• In vitro assessment of TLR7/8 agonistic activity and cytokine secretion (IFN-α, IFN-γ, TNF-α, IL-1β, IL-12p40, IP-10) in human peripheral blood mononuclear cells.
• In vivo evaluation of tumor growth suppression in CT26 tumor-bearing mice.
• Assessment of combination therapy with anti-PD-1/PD-L1 antibodies.

Main Results:

• Novel pyrido[3,2-d]pyrimidine compounds demonstrated potent and near-equivalent TLR7/8 dual agonistic activity.
• Compounds 24e and 25a significantly induced key pro-inflammatory cytokines in vitro.
• Compounds 24e, 24m, and 25a suppressed tumor growth in vivo and enhanced anti-PD-1/PD-L1 blockade efficacy.
• Combination of compound 24e with an anti-PD-L1 antibody resulted in complete tumor regression.

Conclusions:

• The synthesized pyrido[3,2-d]pyrimidine-based TLR7/8 agonists show significant potential for cancer immunotherapy.
• These compounds can be utilized as single agents or in combination with immune checkpoint inhibitors like anti-PD-1/PD-L1 antibodies for enhanced antitumor effects.