Design, Synthesis, and Structure-Activity Relationship of N-Aryl-N′-(thiophen-2-yl)thiourea Derivatives as Novel and Specific Human TLR1/2 Agonists for Potential Cancer Immunotherapy
Design, Synthesis, and Structure-Activity Relationship of N-Aryl-N′-(thiophen-2-yl)thiourea Derivatives as Novel and Specific Human TLR1/2 Agonists for Potential Cancer Immunotherapy
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DOI：
10.1021/acs.jmedchem.0c02266
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发表时间：
2021-05-24
影响因子：
7.3
通讯作者：
Cheng, Kui
中科院分区：
文献类型：
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作者：
Chen, Zhipeng;Zhang, Lina;Cheng, Kui
先前对1000万种化合物的虚拟筛选产生了两种新的非脂肽样化学型作为TLR 2激动剂。在此，我们介绍了我们的初始命中物1-苯基-3-（噻吩-2-基）脲的化学优化，结果将SMU-C80（EC 50 = 31.02 +/- 1.01 nM）鉴定为TLR 2特异性激动剂，其生物活性提高了370倍。机制研究表明，SMU-C80通过TLR 1/2募集衔接蛋白MyD 88并触发NF-κ B途径从人细胞而非鼠细胞释放细胞因子如TNF-α和IL-1 β。据我们所知，这是迄今为止报道的第一个物种特异性TLR 1/2激动剂。此外，SMU-C80在体外增加T、B和NK细胞的百分比，并激活免疫细胞，这在体外抑制癌细胞生长。总之，我们获得了一种高效和特异性的人TLR 1/2激动剂，其通过MyD 88和NF-κ B途径起作用，促进细胞因子释放和免疫细胞的同时激活，从而影响癌细胞的凋亡。
The previous virtual screening of ten million compounds yielded two novel nonlipopeptide-like chemotypes as TLR2 agonists. Herein, we present the chemical optimization of our initial hit, 1-phenyl-3-(thiophen-2-yl)urea, which resulted in the identification of SMU-C80 (EC50 = 31.02 +/- 1.01 nM) as a TLR2-specific agonist with a 370-fold improvement in bioactivity. Mechanistic studies revealed that SMU-C80, through TLR1/2, recruits the adaptor protein MyD88 and triggers the NF-kappa B pathway to release cytokines such as TNF-alpha and IL-1 beta from human, but not murine, cells. To the best of our knowledge, it is the first species-specific TLR1/2 agonist reported until now. Moreover, SMU-C80 increased the percentage of T, B, and NK cells ex vivo and activated the immune cells, which suppressed cancer cell growth in vitro. In summary, we obtained a highly efficient and specific human TLR1/2 agonist that acts through the MyD88 and NF-kappa B pathway, facilitating cytokine release and the simultaneous activation of immune cells that in turn affects the apoptosis of cancer cells.