indoleamine 2,3-dioxygenase 1 | 1.13.11.- Dioxygenases | IUPHAR/BPS Guide to PHARMACOLOGY

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indoleamine 2,3-dioxygenase 1

target has curated data in GtoImmuPdb

Target id: 2829

Nomenclature: indoleamine 2,3-dioxygenase 1

Abbreviated Name: IDO1

Family: 1.13.11.- Dioxygenases

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 403 8p12-p11 IDO1 indoleamine 2,3-dioxygenase 1 2,20
Mouse - 407 8 A2 Ido1 indoleamine 2,3-dioxygenase 1
Rat - 407 16q12.5 Ido1 indoleamine 2,3-dioxygenase 1
Gene and Protein Information Comments
Two isoforms of mouse Ido1 have been identified. We list the longer of the two, isoform 1 in the table above. The shorter isoform has only 316 amino acids.
Previous and Unofficial Names
INDO | indoleamine-pyrrole 2,3 dioxygenase | IDO-1 | IDO | indoleamine 2
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the indoleamine 2,3-dioxygenagse 1 (IDO1) complexed with Amg-1.
PDB Id:  4PK5
Ligand:  amg-1
Resolution:  2.79Å
Species:  Human
References:  24
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of Human IDO1 bound to navoximod (NLG-919)
PDB Id:  6O3I
Ligand:  navoximod
Resolution:  2.69Å
Species:  Human
References:  11
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the indoleamine 2,3-dioxygenase 1 (IDO1) in complexed with ferric heme and Epacadostat
PDB Id:  6E40
Ligand:  epacadostat
Resolution:  2.306Å
Species:  Human
References:  15
Enzyme Reaction
EC Number: 1.13.11.52

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 8u [PMID: 31999451] Hs Inhibition 7.1 pKd 8
pKd 7.1 (Kd 8x10-8 M) [8]
Description: Binding dissociation constant determined for recombinant human IDO1 by SPR analysis.
navoximod Hs Inhibition 8.2 pKi 11
pKi 8.2 (Ki 5.8x10-9 M) [11]
tryptanthrin 5i Hs Inhibition 7.3 pKi 13
pKi 7.3 (Ki 5.4x10-8 M) [13]
tryptanthrin Hs Inhibition 5.3 pKi 26
pKi 5.3 (Ki 4.81x10-6 M) [26]
necrostatin-1 Hs Inhibition 4.9 pKi 19
pKi 4.9 (Ki 1.16x10-5 M) [19]
Description: Using a purified recombinant human IDO enzyme for in vitro>/i> assays.
1-methyl-L-tryptophan Hs Inhibition 4.4 pKi 26
pKi 4.4 (Ki 4.23x10-5 M) [26]
beta-carboline Hs Inhibition 0.9 pKi 3
pKi 0.9 (Ki 1.2x10-1 M) [3]
epacadostat Hs Inhibition 7.2 pIC50 27
pIC50 7.2 (IC50 6.7x10-8 M) [27]
tryptanthrin 5i Hs Inhibition 7.0 pIC50 13
pIC50 7.0 (IC50 1.03x10-7 M) [13]
PF-06840003 Hs Inhibition 6.8 pIC50 1
pIC50 6.8 (IC50 1.5x10-7 M) [1]
Description: Measuring inhibition of IDO1-induced kynurenine production in vitro.
LW106 Hs Inhibition 5.8 pIC50 4
pIC50 5.8 (IC50 1.57x10-6 M) [4]
Description: Measuring enzyme activity in IFNγ-stimulated HeLa cells.
amg-1 Hs Inhibition 5.5 pIC50 16
pIC50 5.5 (IC50 3x10-6 M) [16]
linrodostat Hs Inhibition - - 21
[21]
Immunopharmacology Comments
The indoleamine 2,3 dioxygenase (IDO) branch of the kynurenine (KYN) pathway of tryptophan metabolism has been intensely studied in relation to immune tolerance and allergy. IDO is generally considered to be a tolerogenic, immunosuppressive enzyme, that is induced by IFN-γ. It provides a negative feedback pathway that limits uncontrolled immune responses. Its immunosuppressive actions arise from its promotion of tryptophan depletion, and elevation of KYN metabolite levels. The aryl hydrocarbon receptor serves as a receptor for KYN and should be considered when evaluating the IDO-KYN pathway in immune homeostasis and its potential to modulate innate and adaptive immune responses [9].

IDO1 expression is increased by IFN-γ and IL-6 [12] (the latter in the presence of a histone deacetylase inhibitor). It is proposed that upregulating IDO1 via HDAC inhibition may be a therapeutic approach for the acute lethal idiopathic pulmonary syndrome that is a complication following allogeneic hematopoietic stem cell transplantation [12].

In the tumour microenvironment, depletion of tryptophan (catalysed by tumour-expressed IDO1) promotes Treg cell differentiation, suppresses the immune response and decreases dendritic cell function, thus creating a tolerogenic environment in which the cancer cells can survive and proliferate. Since IDO1 inhibitors have been shown to reverse this escape mechanism, ID01 has emerged as a promising molecular target for the development of novel agents as cancer immunotherapeutics [7], as well as for the treatment of other diseases that are characterised by the reduction of local tryptophan levels. The applicability of ID01 inhibition has been shown in preclinical models of diseases including arthritis, ischemia-reperfusion injury, endotoxin shock, human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, airway inflammation, and cancer [6,25]. However, clinical therapeutic efficacy has proven elusive [10].
Cell Type Associations
Immuno Cell Type:  Dendritic cells
Cell Ontology Term:   dendritic cell (CL:0000451)
Langerhans cell (CL:0000453)
References:  5,9
Immuno Process Associations
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 4 GO processes
GO:0046007 negative regulation of activated T cell proliferation IMP
GO:0070234 positive regulation of T cell apoptotic process IMP
click arrow to show/hide IEA associations
GO:0042130 negative regulation of T cell proliferation IEA
GO:0070233 negative regulation of T cell apoptotic process IEA
Immuno Process:  Inflammation
GO Annotations:  Associated to 3 GO processes, IEA only
GO:0006954 inflammatory response IMP
click arrow to show/hide IEA associations
GO:0002534 cytokine production involved in inflammatory response IEA
GO:0002678 positive regulation of chronic inflammatory response IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 5 GO processes, IEA only
GO:0046007 negative regulation of activated T cell proliferation IMP
click arrow to show/hide IEA associations
GO:0002666 positive regulation of T cell tolerance induction IEA
GO:0002678 positive regulation of chronic inflammatory response IEA
GO:0002830 positive regulation of type 2 immune response IEA
GO:0042130 negative regulation of T cell proliferation IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0002666 positive regulation of T cell tolerance induction IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 3 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0002534 cytokine production involved in inflammatory response IEA
GO:0032693 negative regulation of interleukin-10 production IEA
GO:0032735 positive regulation of interleukin-12 production IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 2 GO processes, IEA only
GO:0046007 negative regulation of activated T cell proliferation IMP
click arrow to show/hide IEA associations
GO:0042130 negative regulation of T cell proliferation IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 2 GO processes, IEA only
GO:0046007 negative regulation of activated T cell proliferation IMP
click arrow to show/hide IEA associations
GO:0042130 negative regulation of T cell proliferation IEA
Physiological Functions
Indoleamine 2,3-dioxygenase 1 catalyzes the degradation of L-tryptophan via the reaction L-tryptophan + O2 <=> N-formyl-L-kynurenine. L-tryptophan has an immunosuppressive effect.
Species:  Human
Tissue:  Macrophages
References:  17
IDO expression at the maternal–fetal interface depletes L-tryptophan, an effect which inhibits activation of maternal T-cells in resopnse to fetal alloantigens, thereby preventing rejection of the fetus.
Species:  Mouse
Tissue:  Decidua, placenta
References:  17
IDO expression by tumour cells, depletes L-tryptophan in the tumour microenvironment blocks T-cell proliferation thereby allowing tumour cells to evade the immune response.
Species:  Human
Tissue:  Melanoma cells, pancreatic cancer cells, non-small cell lung cancer cells, laryngeal carcinoma cells, pharyngeal squamous-cell carcinoma cells.
References:  25
General Comments
IDO1 is a rate-limiting enzyme of tryptophan catabolism along the kynurenine pathway. IDO1 catabolises both the L- and D- enantiomers of tryptophan, but shows preference for L-tryptophan. Additional IDO1 substrates include indoleamines such as serotonin, melatonin, and tryptamine [22].
IDO1 emerged as an important new therapeutic target for the treatment of cancer, neurological disorders, and other diseases that are characterized by pathological tryptophan metabolism. Despite encouraging anti-tumour activity in preclinical models and good tolerability and encouraging efficacy in early stage clinical trials, especially in combination with immune checkpoint inhibitors [18], the potential of IDO1 inhibitors may not be translated to later stage clinical efficacy. Results from the Phase 3 ECHO-301 study (NCT02752074) found no evidence that epacadostat provides any increased benefit compared to pembrolizumab alone in patients with unresectable or metastatic melanoma [14]. This failure has led to a re-evaluation of the utility of IDO1 inhibition as an adjunct to checkpoint inhibition in immuno-oncology [23] (see also IDO Inhibitors Hit a Wall on Derek Lowe's In The Pipeline blog, April 9, 2018).

References

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1. Crosignani S, Cauwenberghs S, Driessens G, Deroose F. (2015) Pyrrolidine-2,5-dione derivatives, pharmaceutical compositions and methods for use as ido1 inhibitors. Patent number: WO2015173764. Assignee: Iteos Therapeutics. Priority date: 15/05/2014. Publication date: 19/11/2015.

2. Dai W, Gupta SL. (1990) Molecular cloning, sequencing and expression of human interferon-gamma-inducible indoleamine 2,3-dioxygenase cDNA. Biochem. Biophys. Res. Commun., 168 (1): 1-8. [PMID:2109605]

3. Dolušić E, Larrieu P, Blanc S, Sapunaric F, Norberg B, Moineaux L, Colette D, Stroobant V, Pilotte L, Colau D et al.. (2011) Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors. Bioorg. Med. Chem., 19 (4): 1550-61. [PMID:21269836]

4. Fu R, Zhang YW, Li HM, Lv WC, Zhao L, Guo QL, Lu T, Weiss SJ, Li ZY, Wu ZQ. (2018) LW106, a novel indoleamine 2,3-dioxygenase 1 inhibitor, suppresses tumour progression by limiting stroma-immune crosstalk and cancer stem cell enrichment in tumour micro-environment. Br. J. Pharmacol., 175 (14): 3034-3049. [PMID:29722898]

5. Heitger A. (2011) Regulation of expression and function of IDO in human dendritic cells. Curr. Med. Chem., 18 (15): 2222-33. [PMID:21517757]

6. Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. (2013) Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med., 210 (7): 1389-402. [PMID:23752227]

7. Hornyák L, Dobos N, Koncz G, Karányi Z, Páll D, Szabó Z, Halmos G, Székvölgyi L. (2018) The Role of Indoleamine-2,3-Dioxygenase in Cancer Development, Diagnostics, and Therapy. Front Immunol, 9: 151. [PMID:29445380]

8. Huang R, Jing X, Huang X, Pan Y, Fang Y, Liang G, Liao Z, Wang H, Chen Z, Zhang Y. (2020) Bifunctional Naphthoquinone Aromatic Amide-Oxime Derivatives Exert Combined Immunotherapeutic and Antitumor Effects through Simultaneous Targeting of Indoleamine-2,3-dioxygenase and Signal Transducer and Activator of Transcription 3. J. Med. Chem., 63 (4): 1544-1563. [PMID:31999451]

9. Koch S, Stroisch TJ, Vorac J, Herrmann N, Leib N, Schnautz S, Kirins H, Förster I, Weighardt H, Bieber T. (2017) AhR mediates an anti-inflammatory feedback mechanism in human Langerhans cells involving FcεRI and IDO. Allergy, 72 (11): 1686-1693. [PMID:28376268]

10. Komiya T, Huang CH. (2018) Updates in the Clinical Development of Epacadostat and Other Indoleamine 2,3-Dioxygenase 1 Inhibitors (IDO1) for Human Cancers. Front Oncol, 8: 423. [PMID:30338242]

11. Kumar S, Waldo JP, Jaipuri FA, Marcinowicz A, Van Allen C, Adams J, Kesharwani T, Zhang X, Metz R, Oh AJ et al.. (2019) Discovery of Clinical Candidate (1R,4r)-4-((R)-2-((S)-6-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a Potent and Selective Inhibitor of Indoleamine 2,3-Dioxygenase 1. J. Med. Chem., 62 (14): 6705-6733. [PMID:31264862]

12. Lee SM, Park HY, Suh YS, Yoon EH, Kim J, Jang WH, Lee WS, Park SG, Choi IW, Choi I et al.. (2017) Inhibition of acute lethal pulmonary inflammation by the IDO-AhR pathway. Proc. Natl. Acad. Sci. U.S.A., 114 (29): E5881-E5890. [PMID:28673995]

13. Li J, Li Y, Yang D, Hu N, Guo Z, Kuang C, Yang Q. (2016) Establishment of a human indoleamine 2, 3-dioxygenase 2 (hIDO2) bioassay system and discovery of tryptanthrin derivatives as potent hIDO2 inhibitors. Eur J Med Chem, 123: 171-179. [PMID:27475108]

14. Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, Arance A, Carlino MS, Grob JJ, Kim TM et al.. (2019) Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol., 20 (8): 1083-1097. [PMID:31221619]

15. Luo S, Xu K, Xiang S, Chen J, Chen C, Guo C, Tong Y, Tong L. (2018) High-resolution structures of inhibitor complexes of human indoleamine 2,3-dioxygenase 1 in a new crystal form. Acta Crystallogr F Struct Biol Commun, 74 (Pt 11): 717-724. [PMID:30387777]

16. Meininger D, Zalameda L, Liu Y, Stepan LP, Borges L, McCarter JD, Sutherland CL. (2011) Purification and kinetic characterization of human indoleamine 2,3-dioxygenases 1 and 2 (IDO1 and IDO2) and discovery of selective IDO1 inhibitors. Biochim. Biophys. Acta, 1814 (12): 1947-54. [PMID:21835273]

17. Mellor AL, Munn DH. (1999) Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation?. Immunol. Today, 20 (10): 469-73. [PMID:10500295]

18. Mitchell TC, Hamid O, Smith DC, Bauer TM, Wasser JS, Olszanski AJ, Luke JJ, Balmanoukian AS, Schmidt EV, Zhao Y et al.. (2018) Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037). J. Clin. Oncol., 36 (32): 3223-3230. [PMID:30265610]

19. Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC. (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat. Med., 11 (3): 312-9. [PMID:15711557]

20. Najfeld V, Menninger J, Muhleman D, Comings DE, Gupta SL. (1993) Localization of indoleamine 2,3-dioxygenase gene (INDO) to chromosome 8p12-->p11 by fluorescent in situ hybridization. Cytogenet. Cell Genet., 64 (3-4): 231-2. [PMID:8404046]

21. Nelp MT, Kates PA, Hunt JT, Newitt JA, Balog A, Maley D, Zhu X, Abell L, Allentoff A, Borzilleri R et al.. (2018) Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form. Proc. Natl. Acad. Sci. U.S.A., 115 (13): 3249-3254. [PMID:29531094]

22. Shimizu T, Nomiyama S, Hirata F, Hayaishi O. (1978) Indoleamine 2,3-dioxygenase. Purification and some properties. J. Biol. Chem., 253 (13): 4700-6. [PMID:26687]

23. Sondak VK, Khushalani NI. (2019) Echoes of a failure: what lessons can we learn?. Lancet Oncol., 20 (8): 1037-1039. [PMID:31221617]

24. Tojo S, Kohno T, Tanaka T, Kamioka S, Ota Y, Ishii T, Kamimoto K, Asano S, Isobe Y. (2014) Crystal Structures and Structure-Activity Relationships of Imidazothiazole Derivatives as IDO1 Inhibitors. ACS Med Chem Lett, 5 (10): 1119-23. [PMID:25313323]

25. Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ. (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med., 9 (10): 1269-74. [PMID:14502282]

26. Yang S, Li X, Hu F, Li Y, Yang Y, Yan J, Kuang C, Yang Q. (2013) Discovery of tryptanthrin derivatives as potent inhibitors of indoleamine 2,3-dioxygenase with therapeutic activity in Lewis lung cancer (LLC) tumor-bearing mice. J. Med. Chem., 56 (21): 8321-31. [PMID:24099220]

27. Yue EW, Douty B, Wayland B, Bower M, Liu X, Leffet L, Wang Q, Bowman KJ, Hansbury MJ, Liu C et al.. (2009) Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model. J. Med. Chem., 52 (23): 7364-7. [PMID:19507862]

How to cite this page

1.13.11.- Dioxygenases: indoleamine 2,3-dioxygenase 1. Last modified on 18/03/2020. Accessed on 16/07/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2829.