Discovery of the First Selective IDO2 Inhibitor As Novel Immunotherapeutic Avenues for Rheumatoid Arthritis

Indoleamine 2,3-dioxygenase 2 (IDO2), a closely related homologue of well-studied immunomodulatory enzyme IDO1, has been identified as a pathogenic mediator of inflammatory autoimmunity in preclinical models. Therapeutic targeting IDO2 in autoimmune diseases has been challenging due to the lack of s...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 65; no. 21; pp. 14348 - 14365
Main Authors:	He, Guangchao, Wan, Sheng, Wu, Yunze, Chu, Zhaoxing, Shen, Hui, Zhang, Shan, Chen, Linya, Bao, Zijing, Gu, Shuhui, Huang, Junzhang, Huang, Lei, Gong, Guoqing, Zou, Yi, Zhu, Qihua, Xu, Yungen
Format:	Journal Article
Language:	English
Published:	American Chemical Society 10-11-2022
Online Access:	Get full text
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Summary:	Indoleamine 2,3-dioxygenase 2 (IDO2), a closely related homologue of well-studied immunomodulatory enzyme IDO1, has been identified as a pathogenic mediator of inflammatory autoimmunity in preclinical models. Therapeutic targeting IDO2 in autoimmune diseases has been challenging due to the lack of small-molecule IDO2 inhibitors. Here, based on our previously developed IDO1/IDO2 dual inhibitor, guided by the homology model of the IDO2 structure, we discovered compound 22, the most potent inhibitor targeting IDO2 with good in vitro inhibitory activity (IDO2 IC50 = 112 nM). Notably, treatment with 22 alleviated disease severity and reduced inflammatory cytokines in both the collagen-induced arthritis (CIA) mice model and adjuvant arthritis (AA) rat model. Our study offered for the first time a selective small-molecule IDO2 inhibitor 22 with IC50 at the nanomolar level, which may be used not only as a candidate compound for the treatment of autoimmune diseases but also as a tool compound for further IDO2-related mechanistic study.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.2c00263