a Department of Medicinal Chemistry, School of Medicine , Nankai University , Tianjin , China.
b State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering , Nankai University , Tianjin , China.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):1089-1094. doi: 10.1080/14756366.2018.1471688.
Indoleamine 2,3-dioxygenase 1 (IDO1) activity links to immune escape of cancers. Inhibition of IDO1 provides a new approach for cancer treatment. Most clinical IDO1 drugs show marginal efficacy as single agents. On basis of molecular docking and pharmacophore modelling, a novel inhibitor Roxyl-WL was discovered with a half maximal inhibitory concentration (IC50) value of 1 nM against IDO1 and 10-100-fold increased potent activity compared with IDO1 drugs in clinical trials. Roxyl-WL displayed excellent kinase spectrum selectivity with no activity out of the 337 protein kinases. In vitro, Roxyl-WL effectively augmented the proliferation of T cells and reduced the number of regulatory T cell (Tregs).When administered to melanoma (B16F10) tumor-bearing mice orally, Roxyl-WL significantly suppressed tumor growth and induced immune response.
色氨酸 2,3-双加氧酶 1（IDO1）的活性与癌症的免疫逃逸有关。抑制 IDO1 为癌症治疗提供了一种新方法。大多数临床 IDO1 药物作为单一药物的疗效都很有限。基于分子对接和药效团建模，发现了一种新型抑制剂 Roxyl-WL，其对 IDO1 的半数最大抑制浓度（IC50）值为 1nM，与临床试验中的 IDO1 药物相比，其活性增加了 10-100 倍。Roxyl-WL 对激酶谱具有优异的选择性，在 337 种蛋白激酶中没有活性。在体外，Roxyl-WL 可有效增强 T 细胞的增殖并减少调节性 T 细胞（Tregs）的数量。当以口服方式施用于患有黑色素瘤（B16F10）的荷瘤小鼠时，Roxyl-WL 可显著抑制肿瘤生长并诱导免疫反应。
