Discovery of Novel Small-Molecule Toll-like Receptor 2 Agonists via a Scaffold Hopping Strategy

Toll-like receptor 2 (TLR2) has emerged as a promising therapeutic target for reversing tumor immunosuppression, and its agonists have shown great potential for cancer immunotherapy. Herein, we report a series of novel TLR2 agonists developed via scaffold hopping of SMU-Z1 and systematic structure-activity relationship (SAR) studies. Among these, C10 (EC₅₀ = 0.035 μM) was identified as the most promising compound, exhibiting potent agonistic activity. Notably, C10 (HLM t₁/₂ > 60 min) achieves significantly improved metabolic stability, compared with SMU-Z1 (HLM t _1/2 = 31.4 min). C10 is a selective TLR2/1 agonist without activating TLR3, TLR4, TLR7 or TLR8. Moreover, C10 induced the secretion of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in human immune cells. Collectively, these data position C10 as a promising TLR2 agonist to further develop an immunotherapy candidate.