Discovery of potent IDO1 inhibitors derived from tryptophan using scaffold-hopping and structure-based design approaches
Discovery of potent IDO1 inhibitors derived from tryptophan using scaffold-hopping and structure-based design approaches
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使用支架跳跃和基于结构的设计方法发现源自色氨酸的有效 IDO1 抑制剂
DOI：
10.1016/j.ejmech.2017.06.039
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发表时间：
2017
影响因子：
6.7
通讯作者：
Lai Yisheng
中科院分区：
文献类型：
--
作者：
Zou Yi;Wang Yan;Wang Fang;Luo Minghao;Li Yuezhen;Liu Wen;Huang Zhangjian;Zhang Yihua;Guo Wenjie;Xu Qiang;Lai Yisheng
吲哚胺2，3-双加氧酶1（IDO 1）经常被肿瘤劫持以逃避宿主免疫反应，并且该酶现在已被牢固地确立为癌症免疫治疗的有吸引力的靶点。为了筛选适合药物开发的新型IDO 1抑制剂，利用骨架跳跃策略结合平均静电势计算设计了新型苯并恶唑啉酮衍生物。其中，化合物7 e、7 f和9 c在低微摩尔范围内表现出抑制效力，并且对HeLa细胞显示出可忽略的水平的细胞毒性。这三种化合物均能促进B16 F1细胞和幼稚T细胞共培养体系中T淋巴细胞的增殖，并导致调节性T细胞数量的显著减少。随后的光谱实验表明，这些苯并恶唑啉酮与血红素铁形成配位键，以稳定复合物。这项研究表明，苯并恶唑啉酮是一个有趣的支架，发现新的IDO 1抑制剂，这些化合物是有吸引力的候选人，为进一步开发。
Indoleamine 2,3-dioxygenase 1 (IDO1) is frequently hijacked by tumors to escape the host immune response, and the enzyme is now firmly established as an attractive target for cancer immunotherapy. To identify novel IDO1 inhibitors suitable for drug development, a scaffold-hopping strategy combined with the average electrostatic potentials calculation was ultilized to design novel benzoxazolinone derivatives. Among these, compounds7e,7fand9cexhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against HeLa cells. Treatment with these three compounds promoted the proliferation of T lymphocyte and led to the dramatic decrease of regulatory T cells in the B16F1 cells and naïve T cells co-culture system. Subsequent spectroscopic experiments suggested that these benzoxazolinones formed a coordinate bond with the heme iron to stabilize the complex. This study suggested that the benzoxazolinone was an interesting scaffold for discovering novel IDO1 inhibitors, and these compounds are attractive candidates for further development.