Design and optimisation of a small-molecule TLR2/4 antagonist for anti-tumour therapy,RSC Medicinal Chemistry

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Design and optimisation of a small-molecule TLR2/4 antagonist for anti-tumour therapy
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-09-07 , DOI: 10.1039/d1md00175b
Qun Xu ₁ , Tian Li ₂ , Hekai Chen ₁ , Jun Kong ₁ , Liwei Zhang ₂ , Hang Yin _{1,

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Affiliation

In anti-tumour therapy, the toll-like receptor 2/4 (TLR2/4) signalling pathway has been a double-edged sword. TLR2/4 agonists are commonly considered adjuvants for immune stimulation, whereas TLR2/4 antagonists demonstrate more feasibility for anti-tumour therapy under specific chronic inflammatory situations. In individuals with cancer retaliatory proliferation and metastasis after surgery, blocking the TLR2/4 signalling pathway may produce favourable prognosis for patients. Therefore, here, we developed a small-molecule co-inhibitor that targets the TLR2/4 signalling pathway. After high-throughput screening of a compound library containing 14 400 small molecules, followed by hit-to-lead structural optimisation, we finally obtained the compound TX-33, which has effective inhibitory properties against the TLR2/4 signalling pathways. This compound was found to significantly inhibit multiple pro-inflammatory cytokines released by RAW264.7 cells. This was followed by TX-33 demonstrating promising efficacy in subsequent anti-tumour experiments. The current results provide a novel understanding of the role of TLR2/4 in cancer and a novel strategy for anti-tumour therapy.

中文翻译：

用于抗肿瘤治疗的小分子TLR2/4拮抗剂的设计和优化

在抗肿瘤治疗中，Toll样受体2/4（TLR2/4）信号通路是一把双刃剑。TLR2/4 激动剂通常被认为是免疫刺激的佐剂，而 TLR2/4 拮抗剂在特定慢性炎症情况下显示出更多的抗肿瘤治疗可行性。在手术后患有癌症报复性增殖和转移的个体中，阻断 TLR2/4 信号通路可能会给患者带来良好的预后。因此，在这里，我们开发了一种针对 TLR2/4 信号通路的小分子联合抑制剂。经过对含有14 400个小分子的化合物库进行高通量筛选，并进行hit-to-lead结构优化，最终获得了对TLR2/4信号通路具有有效抑制作用的化合物TX-33。该化合物被发现能显着抑制 RAW264.7 细胞释放的多种促炎细胞因子。随后 TX-33 在随后的抗肿瘤实验中显示出有希望的功效。目前的结果为 TLR2/4 在癌症中的作用提供了新的认识，并为抗肿瘤治疗提供了新的策略。

更新日期：2021-09-07

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