SIB Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, Switzerland.
Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):1773-1811. doi: 10.1080/14756366.2022.2089665.
The haem enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the rate-limiting step in the kynurenine pathway of tryptophan metabolism and plays an essential role in immunity, neuronal function, and ageing. Expression of IDO1 in cancer cells results in the suppression of an immune response, and therefore IDO1 inhibitors have been developed for use in anti-cancer immunotherapy. Here, we report an extension of our previously described highly efficient haem-binding 1,2,3-triazole and 1,2,4-triazole inhibitor series, the best compound having both enzymatic and cellular IC values of 34 nM. We provide enzymatic inhibition data for almost 100 new compounds and X-ray diffraction data for one compound in complex with IDO1. Structural and computational studies explain the dramatic drop in activity upon extension to pocket B, which has been observed in diverse haem-binding inhibitor scaffolds. Our data provides important insights for future IDO1 inhibitor design.
血红素酶吲哚胺 2,3-双加氧酶 1（IDO1）催化色氨酸代谢中犬尿氨酸途径的限速步骤，在免疫、神经元功能和衰老中发挥着重要作用。癌细胞中 IDO1 的表达导致免疫反应受到抑制，因此开发了 IDO1 抑制剂用于癌症免疫治疗。在这里，我们报告了对我们之前描述的高效血红素结合 1,2,3-三唑和 1,2,4-三唑抑制剂系列的扩展，最好的化合物在酶和细胞 IC 值方面均为 34 nM。我们提供了近 100 种新化合物的酶抑制数据和一种与 IDO1 结合的化合物的 X 射线衍射数据。结构和计算研究解释了在扩展到口袋 B 时活性的急剧下降，这在各种血红素结合抑制剂支架中都有观察到。我们的数据为未来的 IDO1 抑制剂设计提供了重要的见解。
