Dual-target inhibitors of indoleamine 2, 3 dioxygenase 1 (Ido1): A promising direction in cancer immunotherapy

Eur J Med Chem. 2022 Aug 5:238:114524. doi: 10.1016/j.ejmech.2022.114524.

Ya Zhang ¹, Zelin Hu ¹, Jifa Zhang ², Changyu Ren ³, Yuxi Wang ⁴

Affiliations

1 Targeted Tracer Research and development laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; College of Life Sciences, Sichuan University, Chengdu, 610064, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
2 Targeted Tracer Research and development laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
3 Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu, Sichuan, 611130, China. Electronic address: renchangyu1991@163.com.
4 Targeted Tracer Research and development laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: yuxiwang@scu.edu.cn.

PMID: 35696861 DOI: 10.1016/j.ejmech.2022.114524

Abstract

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting Enzyme that catalyzes the kynurenine (Kyn) pathway of tryptophan metabolism in the first step, and the kynurenine pathway plays a fundamental role in immunosuppression in the tumor microenvironment. Therefore, researchers are vigorously developing IDO1 inhibitors, hoping to apply them to Cancer Immunotherapy. Nowadays, there have been 11 kinds of IDO1 inhibitors entering clinical trials, among which many inhibitors have shown good tumor inhibitory effect in phase I/II clinical trials. But the phase III study of the most promising IDO1 Inhibitor compound 29 (Epacadostat) failed in 2018, which may be caused by the compensation effect offered by tryptophan 2,3-dioxygenase (TDO), the mismatched drug combination strategies, or Other reasons. Luckily, dual-target inhibitors show great potential and advantages in solving these problems. In recent years, many studies have linked IDO1 to popular targets and selected many IDO1 dual-target inhibitors through pharmacophore fusion strategy and library construction, which enhance the tumor inhibitory effect and reduce side effects. Currently, three kinds of IDO1/TDO dual-target inhibitors have entered clinical trials, and extensive studies have been developing on IDO1 dual-target inhibitors. In this review, we summarize the IDO1 dual-target inhibitors developed in recent years and focus on the structure optimization process, structure-activity relationship, and the efficacy of in vitro and in vivo experiments, shedding a light on the pivotal significance of IDO1 dual-target inhibitors in the treatment of Cancer, providing inspiration for the development of new IDO1 dual-target inhibitors.

Keywords

Cancer immunotherapy; Dual target inhibitor; IDO1; TDO.

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MedChemExpress (MCE) 只为有资质的科研机构、医药企业基于科学研究或药证申报的用途提供医药研发服务，不为任何个人或者非科研性质的、非用于药证申报使用等其他用途提供服务。

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