Discovery of the First Selective IDO2 Inhibitor As Novel Immunotherapeutic Avenues for Rheumatoid Arthritis
Guangchao He, Sheng Wan, Yunze Wu, Zhaoxing Chu, Hui Shen, Shan Zhang, Linya Chen, Zijing Bao, Shu-Hui Gu, Junzhang Huang, Lei Huang, Guoqing Gong, Yi Zou, Qihua Zhu, Yungen Xu
Abstract
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.