Discovery of secondary sulphonamides as IDO1 inhibitors with potent antitumour effects in vivo
Discovery of secondary sulphonamides as IDO1 inhibitors with potent antitumour effects in vivo
复制标题
发现二级磺胺类药物作为 IDO1 抑制剂，具有有效的体内抗肿瘤作用
DOI：
10.1080/14756366.2020.1765165
复制
发表时间：
2020-01-01
影响因子：
5.6
通讯作者：
Lai, Yisheng
中科院分区：
文献类型：
--
作者：
Ge, Shushan;Zhong, Haiqing;Lai, Yisheng
吲哚胺2，3-双加氧酶1（Indoleamine 2，3-dioxygenase 1，IDO 1）作为色氨酸代谢犬尿氨酸途径中的关键限速酶，在肿瘤免疫逃逸中发挥重要作用。本文中，合成了多种仲磺酰胺，并在基于HeLa细胞的IDO 1/犬尿氨酸测定中进行了评价，从而鉴定了新的IDO 1抑制剂。其中，化合物5d、5l和8 g表现出最强的抑制作用，其活性显著高于命中化合物BS-1。体外实验结果表明，这些化合物能恢复T细胞增殖，抑制初始CD 4（+）T细胞向高免疫抑制性FoxP 3（+）调节性T（Treg）细胞的分化，而不影响HeLa细胞的活力和IDO 1蛋白的表达。重要的是，药效学测定显示化合物5d在携带CT 26和B16 F1肿瘤的免疫活性小鼠中具有有效的抗肿瘤作用，但在免疫缺陷小鼠中不具有。在功能上，后续实验证明化合物5d可有效抑制肿瘤细胞增殖，诱导细胞凋亡，上调IFN-γ和颗粒酶B的表达，抑制FoxP 3（+）Treg细胞分化，从而激活免疫系统。因此，化合物5d可能是一个潜在的和有效的药物进行进一步的评估。
Indoleamine 2,3-dioxygenase 1 (IDO1) as a key rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism plays an important role in tumour immune escape. Herein, a variety of secondary sulphonamides were synthesised and evaluated in the HeLa cell-based IDO1/kynurenine assay, leading to the identification of new IDO1 inhibitors. Among them, compounds 5d, 5l and 8g exhibited the strongest inhibitory effect with significantly improved activity over the hit compound BS-1. The in vitro results showed that these compounds could restore the T cell proliferation and inhibit the differentiation of naive CD4(+) T cell into highly immunosuppressive FoxP3(+) regulatory T (Treg) cell without affecting the viability of HeLa cells and the expression of IDO1 protein. Importantly, the pharmacodynamic assay showed that compound 5d possessed potent antitumour effect in both CT26 and B16F1 tumours bearing immunocompetent mice but not in immunodeficient mice. Functionally, subsequent experiments demonstrated that compound 5d could effectively inhibit tumour cell proliferation, induce apoptosis, up-regulate the expression of IFN-gamma and granzyme B, and suppress FoxP3(+) Treg cell differentiation, thereby activate the immune system. Thus, compound 5d could be a potential and efficacious agent for further evaluation.