PMID- 35952367
OWN - NLM
STAT- MEDLINE
DCOM- 20221111
LR  - 20221204
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 65
IP  - 21
DP  - 2022 Nov 10
TI  - Discovery of the First Selective IDO2 Inhibitor As Novel Immunotherapeutic 
      Avenues for Rheumatoid Arthritis.
PG  - 14348-14365
LID - 10.1021/acs.jmedchem.2c00263 [doi]
AB  - 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 IC(50) = 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 IC(50) 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.
FAU - He, Guangchao
AU  - He G
AD  - State Key Laboratory of Natural Medicines, China Pharmaceutical University, 
      Nanjing 210009, China.
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal 
      Chemistry, China Pharmaceutical University, Nanjing 211198, China.
FAU - Wan, Sheng
AU  - Wan S
AD  - Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, 
      China.
FAU - Wu, Yunze
AU  - Wu Y
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal 
      Chemistry, China Pharmaceutical University, Nanjing 211198, China.
FAU - Chu, Zhaoxing
AU  - Chu Z
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal 
      Chemistry, China Pharmaceutical University, Nanjing 211198, China.
FAU - Shen, Hui
AU  - Shen H
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal 
      Chemistry, China Pharmaceutical University, Nanjing 211198, China.
FAU - Zhang, Shan
AU  - Zhang S
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal 
      Chemistry, China Pharmaceutical University, Nanjing 211198, China.
FAU - Chen, Linya
AU  - Chen L
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal 
      Chemistry, China Pharmaceutical University, Nanjing 211198, China.
FAU - Bao, Zijing
AU  - Bao Z
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal 
      Chemistry, China Pharmaceutical University, Nanjing 211198, China.
FAU - Gu, Shuhui
AU  - Gu S
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal 
      Chemistry, China Pharmaceutical University, Nanjing 211198, China.
FAU - Huang, Junzhang
AU  - Huang J
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal 
      Chemistry, China Pharmaceutical University, Nanjing 211198, China.
FAU - Huang, Lei
AU  - Huang L
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal 
      Chemistry, China Pharmaceutical University, Nanjing 211198, China.
FAU - Gong, Guoqing
AU  - Gong G
AD  - Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, 
      China.
FAU - Zou, Yi
AU  - Zou Y
AUID- ORCID: 0000-0001-6782-9380
AD  - State Key Laboratory of Natural Medicines, China Pharmaceutical University, 
      Nanjing 210009, China.
FAU - Zhu, Qihua
AU  - Zhu Q
AUID- ORCID: 0000-0003-4314-4226
AD  - State Key Laboratory of Natural Medicines, China Pharmaceutical University, 
      Nanjing 210009, China.
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal 
      Chemistry, China Pharmaceutical University, Nanjing 211198, China.
FAU - Xu, Yungen
AU  - Xu Y
AUID- ORCID: 0000-0001-6586-8482
AD  - State Key Laboratory of Natural Medicines, China Pharmaceutical University, 
      Nanjing 210009, China.
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal 
      Chemistry, China Pharmaceutical University, Nanjing 211198, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220811
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase)
SB  - IM
MH  - Mice
MH  - Rats
MH  - Animals
MH  - Indoleamine-Pyrrole 2,3,-Dioxygenase
MH  - *Arthritis, Rheumatoid/pathology
MH  - *Arthritis, Experimental/chemically induced/drug therapy
MH  - Immunotherapy
EDAT- 2022/08/12 06:00
MHDA- 2022/11/15 06:00
CRDT- 2022/08/11 17:42
PHST- 2022/08/12 06:00 [pubmed]
PHST- 2022/11/15 06:00 [medline]
PHST- 2022/08/11 17:42 [entrez]
AID - 10.1021/acs.jmedchem.2c00263 [doi]
PST - ppublish
SO  - J Med Chem. 2022 Nov 10;65(21):14348-14365. doi: 10.1021/acs.jmedchem.2c00263. 
      Epub 2022 Aug 11.