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Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy

文献类型： 外文期刊

作者： Yan, Daojing 1 ; Xu, Jiakun 2 ; Wang, Xiang 1 ; Zhang, Jiaxing 3 ; Zhao, Gang 3 ; Lin, Yingwu 4 ; Tan, Xiangshi 1 ;

作者机构： 1.Fudan Univ, Dept Chem, 2005 Songhu Rd, Shanghai 200433, Peoples R China

2.Chinese Acad Fishery Sci, Key Lab Sustainable Dev Polar Fisheries, Minist Agr & Rural Affairs, Yellow Sea Fisheries Res Inst,Lab Marine Drugs &, Qingdao 266071, Peoples R China

3.Chinese Acad Sci, Shanghai Inst Organ Chem, Key Lab Synthet Chem Nat Subst, 345 Lingling Rd, Shanghai 200032, Peoples R China

4.Univ South China, Sch Chem & Chem Engn, Hengyang 421001, Peoples R China

关键词： indoleamine 2,3-dioxygenase 1; metalloenzyme; hemeprotein; inhibitor; molecular docking

期刊名称：INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES （ 影响因子：6.208； 五年影响因子：6.628 ）

ISSN：

年卷期： 2022 年 23 卷 9 期

页码：

收录情况： SCI

摘要： Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive heme enzyme for its significant function in cancer immunotherapy. Potent IDO1 inhibitors have been discovered for decades, whereas no clinical drugs are used for cancer treatment up to now. With the goal of developing medically valuable IDO inhibitors, we performed a systematic study of SAR405838 analogs with a spiro-oxindole skeleton in this study. Based on the expression and purification of human IDO1, the inhibitory activity of spiro-oxindole skeleton compounds to IDO1 was evaluated by IC50 and K-i values. The results demonstrated that inhibitor 3 exhibited the highest IDO1 inhibitory activity with IC50 at 7.9 mu M among all inhibitors, which is similar to six-fold of the positive control (4-PI). Moreover, inhibitor 3 was found to have the most effective inhibition of IDO1 in MCF-7 cancer cells without toxic effects. Molecular docking analysis revealed that the hydrophobic interaction stabilized the binding of inhibitor 3 to the IDO1 active site and made an explanation for the uncompetitive mode of inhibitors. Therefore, this study provides valuable insights into the screen of more potent IDO1 inhibitors for cancer immunotherapy.

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