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

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-20 DOI:10.1021/acsmedchemlett.6c00351

Yueyue Zhu, Longhai Wang, Yuqi Chen, Yujie Wang, Zonglong Chen, Yingxia Li, Wei Zhang

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引用次数: 0

Abstract

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.

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通过支架跳跃策略发现新型小分子toll样受体2激动剂

toll样受体2 （TLR2）已成为逆转肿瘤免疫抑制的有希望的治疗靶点，其激动剂在癌症免疫治疗中具有巨大的潜力。在此，我们报道了一系列通过SMU-Z1的支架跳跃和系统构效关系（SAR）研究开发的新型TLR2激动剂。其中，C10 （EC50 = 0.035μM）被认为是最有希望的化合物，具有较强的拮抗活性。值得注意的是，与SMU-Z1 （HLM t1/2 = 31.4 min）相比，C10 （HLM t1/2 > 60 min）的代谢稳定性显著提高。C10是一种选择性tlr2 /1激动剂，不激活TLR3、TLR4、TLR7或TLR8。此外，C10诱导人免疫细胞分泌il -1β、IL-6和TNF-α等促炎细胞因子。总的来说，这些数据表明C10是一种有前途的TLR2激动剂，可以进一步开发一种免疫治疗候选药物。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.