PMID- 31580660
OWN - NLM
STAT- MEDLINE
DCOM- 20200615
LR  - 20200615
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 62
IP  - 20
DP  - 2019 Oct 24
TI  - N-Benzyl/Aryl Substituted Tryptanthrin as Dual Inhibitors of Indoleamine 
      2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase.
PG  - 9161-9174
LID - 10.1021/acs.jmedchem.9b01079 [doi]
AB  - Indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial and 
      rate-limiting step of the kynurenine pathway of tryptophan catabolism, has 
      emerged as a key target in cancer immunotherapy because of its role in enabling 
      cancers to evade the immune system. Tryptophan 2,3-dioxygenase (TDO) and 
      indoleamine 2,3-dioxygenase 2 (IDO2) catalyze the same reaction and play a 
      potential role in cancer immunotherapy. Starting from our previously discovered 
      tryptanthrin IDO1 inhibitor scaffold, we synthesized novel N-benzyl/aryl 
      substituted tryptanthrin derivatives and evaluated their inhibitory efficacy on 
      IDO1, TDO, and IDO2. Most compounds showed similar high inhibitory activities on 
      both IDO1 and TDO, which were significantly superior over that of IDO2 with 
      magnitude difference. We showed that N-benzyl/aryl substituted tryptanthrin 
      directly interacted with IDO1, TDO, and IDO2, significantly augmented the 
      proliferation of T cells in vitro, blocked the kynurenine pathway, and suppressed 
      tumor growth when administered to LLC and H22 tumor-bearing mice.
FAU - Yang, Dan
AU  - Yang D
AD  - State Key Laboratory of Genetic Engineering, Department of Biochemistry, School 
      of Life Sciences , Fudan University , Songhu Road 2005 , Shanghai 200438 , China.
FAU - Zhang, Shengnan
AU  - Zhang S
AD  - State Key Laboratory of Genetic Engineering, Department of Biochemistry, School 
      of Life Sciences , Fudan University , Songhu Road 2005 , Shanghai 200438 , China.
FAU - Fang, Xin
AU  - Fang X
AD  - State Key Laboratory of Genetic Engineering, Department of Biochemistry, School 
      of Life Sciences , Fudan University , Songhu Road 2005 , Shanghai 200438 , China.
FAU - Guo, Leilei
AU  - Guo L
AD  - State Key Laboratory of Genetic Engineering, Department of Biochemistry, School 
      of Life Sciences , Fudan University , Songhu Road 2005 , Shanghai 200438 , China.
FAU - Hu, Nan
AU  - Hu N
AD  - State Key Laboratory of Genetic Engineering, Department of Biochemistry, School 
      of Life Sciences , Fudan University , Songhu Road 2005 , Shanghai 200438 , China.
FAU - Guo, Zhanling
AU  - Guo Z
AD  - State Key Laboratory of Genetic Engineering, Department of Biochemistry, School 
      of Life Sciences , Fudan University , Songhu Road 2005 , Shanghai 200438 , China.
FAU - Li, Xishuai
AU  - Li X
AD  - State Key Laboratory of Genetic Engineering, Department of Biochemistry, School 
      of Life Sciences , Fudan University , Songhu Road 2005 , Shanghai 200438 , China.
FAU - Yang, Shuangshuang
AU  - Yang S
AD  - State Key Laboratory of Genetic Engineering, Department of Biochemistry, School 
      of Life Sciences , Fudan University , Songhu Road 2005 , Shanghai 200438 , China.
FAU - He, Jin Chao
AU  - He JC
AD  - State Key Laboratory of Genetic Engineering, Department of Biochemistry, School 
      of Life Sciences , Fudan University , Songhu Road 2005 , Shanghai 200438 , China.
FAU - Kuang, Chunxiang
AU  - Kuang C
AD  - Department of Chemistry , Tongji University , Siping Road 1239 , Shanghai 200092 
      , China.
FAU - Yang, Qing
AU  - Yang Q
AUID- ORCID: 0000-0003-4162-922X
AD  - State Key Laboratory of Genetic Engineering, Department of Biochemistry, School 
      of Life Sciences , Fudan University , Songhu Road 2005 , Shanghai 200438 , China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191003
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (IDO1 protein, mouse)
RN  - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase)
RN  - 0 (Isoenzymes)
RN  - 0 (Quinazolines)
RN  - 0 (RNA, Small Interfering)
RN  - 13220-57-0 (tryptanthrine)
RN  - EC 1.13.11.11 (Tryptophan Oxygenase)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Enzyme Inhibitors/*chemistry/pharmacology/therapeutic use
MH  - Female
MH  - Humans
MH  - Indoleamine-Pyrrole 2,3,-Dioxygenase/*antagonists & 
      inhibitors/genetics/metabolism
MH  - Isoenzymes/antagonists & inhibitors/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neoplasms/drug therapy/pathology
MH  - Quinazolines/*chemistry/metabolism/pharmacology
MH  - RNA Interference
MH  - RNA, Small Interfering/metabolism
MH  - Structure-Activity Relationship
MH  - Tryptophan Oxygenase/*antagonists & inhibitors/metabolism
EDAT- 2019/10/04 06:00
MHDA- 2020/06/17 06:00
CRDT- 2019/10/04 06:00
PHST- 2019/10/04 06:00 [pubmed]
PHST- 2020/06/17 06:00 [medline]
PHST- 2019/10/04 06:00 [entrez]
AID - 10.1021/acs.jmedchem.9b01079 [doi]
PST - ppublish
SO  - J Med Chem. 2019 Oct 24;62(20):9161-9174. doi: 10.1021/acs.jmedchem.9b01079. Epub 
      2019 Oct 3.