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

  • J Med Chem. 2022 Aug 11. doi: 10.1021/acs.jmedchem.2c00263.
Guangchao He  1  2 ,  Sheng Wan  3 ,  Yunze Wu  2 ,  Zhaoxing Chu  2 ,  Hui Shen  2 ,  Shan Zhang  2 ,  Linya Chen  2 ,  Zijing Bao  2 ,  Shuhui Gu  2 ,  Junzhang Huang  2 ,  Lei Huang  2 ,  Guoqing Gong  3 ,  Yi Zou  1 ,  Qihua Zhu  1  2 ,  Yungen Xu  1  2
Affiliations
  • 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China.
PMID: 35952367 DOI: 10.1021/acs.jmedchem.2c00263
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.

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