Toll-like receptor (TLR) 2 is a transmembrane receptor that participates in the innate immune response by forming a heterodimer with TLR1 or TLR6. TLR2 agonists play an important role in tumor therapy. Herein, we synthesized a series of 3-(2H-chromen-3-yl)-5-aryl-1,2,4-oxadiazole derivatives and identified WYJ-2 as a potent small and selective molecule agonist of TLR2/1, with an EC₅₀ of 18.57 ± 0.98 nM in human TLR2 and TLR1 transient-cotransfected HEK 293T cells. WYJ-2 promoted the formation of TLR2/1 heterodimers and activated the nuclear factor kappa B (NF-κB) signaling pathway. Moreover, our study indicated that WYJ-2 could induce pyroptosis in cancer cells, mediated by activating the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome. WYJ-2 exhibited effective anti-non-small cell lung cancer (NSCLC) activity in vitro and in vivo. The discovery that activating TLR2/1 induces pyroptosis in cancer cells may highlight the prospects of TLR2/1 agonists in cancer treatment in the future.

中文翻译：

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3-(2H-Chromen-3-基)-5-芳基-1,2,4-恶二唑衍生物的设计与合成作为新型Toll样受体2/1激动剂在体外和体内抑制肺癌

Toll 样受体 (TLR) 2 是一种跨膜受体，通过与 TLR1 或 TLR6 形成异二聚体来参与先天免疫反应。 TLR2激动剂在肿瘤治疗中发挥着重要作用。在此，我们合成了一系列 3-(2 H -chromen-3-yl)-5-aryl-1,2,4-oxadizo 衍生物，并确定 WYJ-2 是 TLR2/1 的有效小分子选择性激动剂，在人 TLR2 和 TLR1 瞬时共转染 HEK 293T 细胞中，EC ₅₀为 18.57 ± 0.98 nM。 WYJ-2促进TLR2/1异二聚体的形成并激活核因子κB（NF-κB）信号通路。此外，我们的研究表明，WYJ-2 可以通过激活 NOD 样受体 Pyrin 结构域 3 (NLRP3) 炎性体介导癌细胞焦亡。 WYJ-2在体外和体内均表现出有效的抗非小细胞肺癌（NSCLC）活性。激活TLR2/1诱导癌细胞焦亡的发现可能凸显TLR2/1激动剂在未来癌症治疗中的前景。