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

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.

Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation–Cancer Interface

“…Overall, of the many trials of IDO inhibitors initiated in the past decade [215,216], most have not progressed beyond Phase 1, or the results have not been published (Table 1). The shift towards selective inhibitors of IDO2 [217,218], dual inhibitors of IDO1 and IDO2 [37] or dual inhibitors of IDO1/2 and TDO [33,35,219] represents a sensible trend toward a definitive assessment of the value of dioxygenase inhibition in cancer. The selective inhibition of IDO2 will be of particular interest, as it promotes expression of IFNγ and increases effector cell invasion of the tumor microenvironment, suppressing growth and cell migration [220].…”

Applications of palladium-catalyzed C–N cross-coupling reactions in pharmaceutical compounds

“…121 was prepared on a large scale through a double C-N bond formation reaction in high yields. 197 CDK7 has a role in transcription and the cell cycle of cancer cells; therefore, research on CDK7 inhibitors and their action mechanism has attracted much attention. A synthesis technique to gain SY-5609 122 was described based on C-N bond formation reactions.…”

Prediction of IDO1 Inhibitors by a Fingerprint‐Based Stacking Ensemble Model Named IDO1Stack

“…Then we stratified the data according to an 8 : 2 ratio into a training set and a test set. Moreover, the external validation set included 222 compounds collected from multiple literature [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] in 2021-2023 in order to evaluate the generalization performance of the model. The number of IDO1 inhibitors and noninhibitors in each data set was listed in Table 1.…”

“…In this work, inhibitor data were collected from the PubChem database [33] and several literature in 2021-2023, [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] essentially covering the currently known IDO1 inhibitors. For compounds collected from the PubChem database, we first removed compounds with no activity values or no literature support, and ensured that the remaining compounds were assigned one of the following activity value types: IC 50 , EC 50 , K d , K i .…”