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.