IDO1 (Indoleamine 2,3-dioxygenase-1) is a heme-containing monomeric oxidoreductase, which can catalyze the degradation of the essential amino acid tryptophan to N-formyl-kynurenine, an intermediate metabolized through a series of steps to form NAD+. IDO1 is considered to play an important role in the induction of tumor immune tolerance, which can regulate the immunosuppressive mechanisms responsible for tumor escape from host immune surveillance. Indoximod is the D-isomer of 1-methyl-tryptophan which is the first IDO inhibitor with Ki value of 7-70μM[1]. The two stereoisomers, 1-methyl-D-Trp (Indoximod) and 1-methyl-L-Trp, possess potentially different biological properties. Compared with 1-methyl-L-Trp, Indoximod exhibited much less potency to IDO enzymic activity on kynurenine production in both purified enzyme and in HeLa cell–based (IC25>100μM) assays. However, Indoximod showed much significant effect on reversing the suppression of T cells created by DCsIDO1+ (dendritic cellsIDO1+), which suggesting that Indoximod may function more efficiently against immunosuppression. Consistent with this, an in vivo study showed that Indoximod (400 mg/kg by oral gavage twice daily, five times a week) was more efficacious as an anticancer agent dependent on IDO gene expression in mouse models of transplantable melanoma and transplantable and autochthonous breast cancer, with combined treatment with chemo-immunotherapy regimens using cyclophosphamide, paclitaxel, or gemcitabine[2].
作用机制
Indoximod is an analogue of D-Trp, which works as a competitive inhibitor for indoleamine 2,3-dioxygenase.[1]
H-D-Trp(1-Me)-OH/1-甲基-D-色氨酸 细胞实验
Cell Line
Concentration
Treated Time
Description
References
SKOV3
50 μM
72 h
evaluate IDO inhibition effect
J Med Chem. 2021 Aug 26;64(16):12132-12151.
CT26
100 μM
48 h
evaluate the effect of 1-MDT conjugation mode on cytotoxicity
J Med Chem. 2021 Aug 26;64(16):12132-12151.
HCT116
100 μM
48 h
evaluate the effect of 1-MDT conjugation mode on cytotoxicity
J Med Chem. 2021 Aug 26;64(16):12132-12151.
PBMC
1mM
12 h
Inhibition of IDO1 activity reverses immune tolerance in septic PBMCs
Front Immunol. 2019 Oct 11;10:2358.
THP-1 human monocytes
1mM
12 h
Inhibition of IDO1 activity, reduction of nuclear NAD levels, and reversal of endotoxin tolerance
Front Immunol. 2019 Oct 11;10:2358.
cortical-striatal neurons
3; 10; 30 and 100 µM
48 h
To evaluate the effect of 1-MT on ZIKV-induced neuronal cell death. 1-MT treatment significantly reduced neuronal cell death at all evaluated concentrations.
Front Immunol. 2021 Jul 15;12:702048.
MCF-7 cells
0–50 μM
3 h
To determine the EC50 of D-1MT in restoring mTOR activity, estimated to be ~70 nM
Oncoimmunology. 2012 Dec 1;1(9):1460-1468.
HeLa cells
60 μM
24 h
To study the effect of IDO-mediated Trp deprivation on mTOR activity, found that D-1MT could restore mTOR activity
Oncoimmunology. 2012 Dec 1;1(9):1460-1468.
THP-1 macrophages
500μM
48 h
Inhibited IDO activity, reversing DPSC/I-DPSC-mediated suppression of TNF-α secretion by macrophages
J Dent Res. 2016 Oct;95(11):1274-81.
Human monocytes
1 mM
24 h
IDO inhibition reversed the effect of abatacept and again permitted the induction of cytokine production by ACPA and RF.
Arthritis Res Ther. 2018 Feb 7;20(1):24.
H-D-Trp(1-Me)-OH/1-甲基-D-色氨酸 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
B16F10 and B78H1·GM-CSF tumor models
Subcutaneous injection
5 mg
Continuous administration from the time of adoptive transfer until the end of the experiment
1MT prevented the induction of T cell unresponsiveness by TDLN DCs by inhibiting IDO activity, thereby restoring T cell responses to tumor antigens.
J Clin Invest. 2004 Jul;114(2):280-90
C57BL/6 mice
Polymicrobial sepsis induced by cecal ligation and puncture (CLP)
Intraperitoneal injection
250 mg/kg
Single dose, monitored for 7 days
Evaluation of the therapeutic effect of 1-MT combined with tryptophan supplementation in sepsis animals, combination therapy significantly improved survival rate
Front Immunol. 2019 Oct 11;10:2358.
A129 mice
ZIKV infection model
Oral
10 mg/mouse
Starting 1 hour after infection, every 24 hours until euthanasia (5 days post-infection)
To evaluate the neuroprotective effect of 1-MT in ZIKV-infected mice. 1-MT treatment reduced microgliosis, astrogliosis, and apoptosis but did not affect viral replication.
Front Immunol. 2021 Jul 15;12:702048.
Rhesus macaques
SIVmac251-infected model
Intraesophageal feeding
45 mg/kg
Starting one day after each MDX-010 injection, for 11 days
To test whether CTLA-4 and IDO blockade decreased immune activation and improved vaccine efficacy. The treatment did not augment vaccine immunogenicity but dramatically increased ART-related toxicity, causing all treated animals to succumb to acute pancreatitis and hyperglycemic coma.
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