a Center for Drug Discovery and Translational Research and Department of Surgery, Beth Israel Deaconess Medical Center , Harvard Medical School , Boston , MA , USA.
Expert Opin Ther Pat. 2018 Apr;28(4):317-330. doi: 10.1080/13543776.2018.1441290. Epub 2018 Feb 23.
Indoleamine 2,3-dioxygenase 1 (IDO1) is overexpressed by cancer cells and the antigen presenting dendritic cells in the tumor microenvironment (TME). Activation of IDO1 depletes tryptophan and produces kynurenine, which induces T cell anergy and suppresses tumor control by the immune system. When combined with an immune checkpoint inhibitor, IDO1 inhibitors have shown promising anticancer activity in preclinical tumor models as well as in early stage clinical trials.
IDO1 inhibitors disclosed in the patent literature from 2013-2017 are categorized, when applicable, according to their structural similarity to the clinical development candidates indoximod and PF-06840003, navoximod, epacadostat, KHK2455 and aryl-1,2-diamines, and BMS-986205 among others, respectively. Representative structures and their IDO1 inhibitory activity are presented to highlight the novelty and activity. Finally, the reported cocrystal structures were analyzed to provide insights for inhibitor-enzyme interactions and guidance for the design and discovery of next generation inhibitors.
This review demonstrates that the structural diversity of new IDO1 inhibitors could be expanded via a number of approaches.
吲哚胺 2,3-双加氧酶 1（IDO1）在肿瘤微环境（TME）中过度表达于癌细胞和抗原呈递树突细胞。IDO1 的激活会消耗色氨酸并产生犬尿氨酸，从而诱导 T 细胞失能并抑制免疫系统对肿瘤的控制。当与免疫检查点抑制剂联合使用时，IDO1 抑制剂在临床前肿瘤模型以及早期临床试验中显示出有希望的抗癌活性。
本专利文献中对 2013-2017 年期间公开的 IDO1 抑制剂进行了分类，根据其与临床开发候选药物吲哚美辛和 PF-06840003、navoximod、epacadostat、KHK2455 和芳基-1,2-二胺以及 BMS-986205 等的结构相似性进行分类，分别。代表性结构及其 IDO1 抑制活性被呈现出来，以突出其新颖性和活性。最后，分析了报道的共晶结构，为抑制剂-酶相互作用提供了见解，并为下一代抑制剂的设计和发现提供了指导。
本综述表明，可以通过多种方法扩展新型 IDO1 抑制剂的结构多样性。
