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 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.