He Guangchao, Wan Sheng, Wu Yunze, Chu Zhaoxing, Shen Hui, Zhang Shan, Chen Linya, Bao Zijing, Gu Shuhui, Huang Junzhang, Huang Lei, Gong Guoqing, Zou Yi, Zhu Qihua, Xu Yungen
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
J Med Chem. 2022 Nov 10;65(21):14348-14365. doi: 10.1021/acs.jmedchem.2c00263. Epub 2022 Aug 11.
Indoleamine 2,3-dioxygenase 2 (IDO2), a closely related homologue of well-studied immunomodulatory enzyme IDO1, has been identified as a pathogenic mediator of inflammatory autoimmunity in preclinical models. Therapeutic targeting IDO2 in autoimmune diseases has been challenging due to the lack of small-molecule IDO2 inhibitors. Here, based on our previously developed IDO1/IDO2 dual inhibitor, guided by the homology model of the IDO2 structure, we discovered compound , the most potent inhibitor targeting IDO2 with good inhibitory activity (IDO2 IC = 112 nM). Notably, treatment with alleviated disease severity and reduced inflammatory cytokines in both the collagen-induced arthritis (CIA) mice model and adjuvant arthritis (AA) rat model. Our study offered for the first time a selective small-molecule IDO2 inhibitor with IC at the nanomolar level, which may be used not only as a candidate compound for the treatment of autoimmune diseases but also as a tool compound for further IDO2-related mechanistic study.
吲哚胺2,3-双加氧酶2（IDO2）是研究充分的免疫调节酶IDO1的紧密同源物，在临床前模型中已被确定为炎性自身免疫的致病介质。由于缺乏小分子IDO2抑制剂，在自身免疫性疾病中靶向IDO2进行治疗一直具有挑战性。在此，基于我们先前开发的IDO1/IDO2双重抑制剂，在IDO2结构同源模型的指导下，我们发现了化合物，它是靶向IDO2的最有效抑制剂，具有良好的抑制活性（IDO2 IC = 112 nM）。值得注意的是，在胶原诱导的关节炎（CIA）小鼠模型和佐剂性关节炎（AA）大鼠模型中，用该化合物治疗均可减轻疾病严重程度并减少炎性细胞因子。我们的研究首次提供了一种纳摩尔水平IC的选择性小分子IDO2抑制剂，它不仅可作为治疗自身免疫性疾病的候选化合物，还可作为进一步进行IDO2相关机制研究的工具化合物。
