IDO2

Summary

IDO2 (indoleamine 2,3-dioxygenase 2, HGNC:27269) is a protein-coding gene on chromosome 8p11.21, encoding Indoleamine 2,3-dioxygenase 2 (Q6ZQW0). Catalyzes the first and rate limiting step of the catabolism of the essential amino acid tryptophan along the kynurenine pathway.

Along with the enzymes encoded by the INDO (MIM 147435) and TDO2 (MIM 191070) genes, the enzyme encoded by the INDOL1 gene metabolizes tryptophan in the kynurenine pathway (Ball et al., 2007 [PubMed 17499941]).

Source: NCBI Gene 169355 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 78 total — 1 pathogenic
• GTEx eGene: eQTL in 7 tissues, sQTL in 3 (q < 0.05)
• ChEMBL bioactivity: 2 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.26 (unconstrained)
• MANE Select transcript: NM_194294
• Interaction hub: 1,788 STRING partners (top 10% of genes corpus-wide)
• Notable: 78 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27269
Approved symbol	IDO2
Name	indoleamine 2,3-dioxygenase 2
Location	8p11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000188676
Ensembl biotype	protein_coding
OMIM	612129
Entrez	169355

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 nonsense_mediated_decay, 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

MANE Select: ENST00000502986

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 2: 2, TSL 5: 1

ENST00000502986, ENST00000343295, ENST00000418094, ENST00000868807, ENST00000976281, ENST00000976282, ENST00000976283, ENST00000976284, ENST00000976285, ENST00000976286, ENST00001119374

RefSeq mRNA: 2 — MANE Select: NM_194294 NM_001395206, NM_194294

CCDS: CCDS6114

Canonical transcript exons

ENST00000502986 — 11 exons

Exon	Start	End
ENSE00001504807	40005327	40005378
ENSE00001650066	39985508	39985522
ENSE00003513766	40015247	40016392
ENSE00003529992	39982652	39982770
ENSE00003565788	39989721	39989838
ENSE00003599615	39949149	39949264
ENSE00003621714	39979067	39979186
ENSE00003664855	39963608	39963703
ENSE00003664905	39987871	39987970
ENSE00003671451	40013565	40013713
ENSE00003964382	39934651	39935218

Expression profiles

Bgee: expression breadth broad, 80 present calls, max score 80.38.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0638 / max 28.0212, expressed in 12 samples.

Highest expression (Bgee): lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis, placenta, lobe of thyroid gland.

Genetic regulation across tissues (GTEx eQTL / sQTL)

IDO2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 7 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

10 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	sqtl	7.2e-21	+0.59	8:40000640:T:TGTTTGTTTGTTTTGA
Liver	sqtl	4.5e-09	-0.70	8:40002154:A:G
Lung	eqtl	1.6e-08	+0.92	8:39944149:A:G
Skin Not Sun Exposed Suprapubic	eqtl	2.3e-07	+0.29	8:39945608:A:C
Testis	sqtl	1.2e-06	-0.50	8:39995775:A:G
Thyroid	eqtl	1.1e-05	-0.19	8:39943919:G:A
Testis	eqtl	7.8e-04	-0.11	8:39991921:T:C
Adipose Visceral Omentum	eqtl	1.3e-03	-0.26	8:39942486:C:A
Skin Sun Exposed Lower leg	eqtl	4.4e-03	-0.21	8:39938290:C:CTATCTA
Small Intestine Terminal Ileum	eqtl	3.3e-02	+0.49	8:40874481:A:G

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
88594	0.0280	6
88606	0.0134	5
88595	0.0107	2
88605	0.0081	1
88596	0.0037	3

Top tissues by expression

showing 100 of 218 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	80.38	gold quality
liver	UBERON:0002107	74.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.04	gold quality
placenta	UBERON:0001987	71.04	gold quality
left lobe of thyroid gland	UBERON:0001120	68.50	gold quality
right lobe of thyroid gland	UBERON:0001119	68.48	gold quality
thyroid gland	UBERON:0002046	66.61	gold quality
vermiform appendix	UBERON:0001154	64.15	gold quality
sperm	CL:0000019	62.09	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	62.08	gold quality
endometrium	UBERON:0001295	61.11	gold quality
lymph node	UBERON:0000029	61.04	gold quality
right testis	UBERON:0004534	60.81	gold quality
left testis	UBERON:0004533	60.63	gold quality
testis	UBERON:0000473	59.04	gold quality
caecum	UBERON:0001153	58.94	gold quality
skin of hip	UBERON:0001554	54.93	gold quality
gall bladder	UBERON:0002110	53.55	gold quality
spleen	UBERON:0002106	53.41	gold quality
rectum	UBERON:0001052	53.40	gold quality
buccal mucosa cell	CL:0002336	53.01	gold quality
mucosa of transverse colon	UBERON:0004991	52.48	gold quality
upper leg skin	UBERON:0004262	50.64	silver quality
sural nerve	UBERON:0015488	50.26	gold quality
bone marrow cell	CL:0002092	50.20	gold quality
colonic epithelium	UBERON:0000397	50.18	gold quality
tonsil	UBERON:0002372	50.09	gold quality
monocyte	CL:0000576	48.92	silver quality
small intestine Peyer’s patch	UBERON:0003454	48.48	gold quality
skin of abdomen	UBERON:0001416	48.32	gold quality
small intestine	UBERON:0002108	47.95	gold quality
uterus	UBERON:0000995	47.92	gold quality
leukocyte	CL:0000738	47.89	silver quality
skin of leg	UBERON:0001511	47.89	gold quality
zone of skin	UBERON:0000014	47.26	gold quality
upper lobe of left lung	UBERON:0008952	46.51	gold quality
upper lobe of lung	UBERON:0008948	46.21	gold quality
granulocyte	CL:0000094	46.20	silver quality
duodenum	UBERON:0002114	46.02	gold quality
lung	UBERON:0002048	44.45	gold quality
bone marrow	UBERON:0002371	44.04	gold quality
right lung	UBERON:0002167	43.81	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
female reproductive system	UBERON:0000474	42.71	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
kidney	UBERON:0002113	41.99	silver quality
adult mammalian kidney	UBERON:0000082	41.93	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
intestine	UBERON:0000160	41.26	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
smooth muscle tissue	UBERON:0001135	40.90	gold quality
urinary bladder	UBERON:0001255	40.85	gold quality
amniotic fluid	UBERON:0000173	40.69	gold quality
muscle tissue	UBERON:0002385	40.62	gold quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
biceps brachii	UBERON:0001507	40.57	gold quality
epithelium of nasopharynx	UBERON:0001951	40.45	gold quality
myocardium	UBERON:0002349	40.45	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
germinal epithelium of ovary	UBERON:0001304	40.33	gold quality
esophagus squamous epithelium	UBERON:0006920	40.29	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	40.27	gold quality
jejunum	UBERON:0002115	40.18	gold quality
cartilage tissue	UBERON:0002418	40.06	gold quality
oviduct epithelium	UBERON:0004804	40.03	gold quality
mammary duct	UBERON:0001765	39.98	gold quality
mucosa of sigmoid colon	UBERON:0004993	39.95	gold quality
skeletal muscle tissue	UBERON:0001134	39.89	gold quality
deltoid	UBERON:0001476	39.83	gold quality
saphenous vein	UBERON:0007318	39.83	gold quality
parotid gland	UBERON:0001831	39.81	gold quality
oocyte	CL:0000023	39.80	gold quality
urethra	UBERON:0000057	39.80	gold quality
heart right ventricle	UBERON:0002080	39.79	gold quality
left adrenal gland cortex	UBERON:0035825	39.78	gold quality
pericardium	UBERON:0002407	39.77	gold quality
layer of synovial tissue	UBERON:0007616	39.77	gold quality
endothelial cell	CL:0000115	39.75	gold quality
cortical plate	UBERON:0005343	39.75	gold quality
synovial joint	UBERON:0002217	39.70	gold quality
dorsal root ganglion	UBERON:0000044	39.68	gold quality
nipple	UBERON:0002030	39.68	gold quality
bronchial epithelial cell	CL:0002328	39.65	gold quality
decidua	UBERON:0002450	39.65	gold quality
penis	UBERON:0000989	39.64	gold quality
gingiva	UBERON:0001828	39.64	gold quality
bronchus	UBERON:0002185	39.64	gold quality
trigeminal ganglion	UBERON:0001675	39.63	gold quality
tendon of biceps brachii	UBERON:0008188	39.60	gold quality
inferior vagus X ganglion	UBERON:0005363	39.57	gold quality
superior surface of tongue	UBERON:0007371	39.56	gold quality
pylorus	UBERON:0001166	39.55	gold quality
renal medulla	UBERON:0000362	39.53	gold quality
pons	UBERON:0000988	39.51	gold quality
thymus	UBERON:0002370	39.50	gold quality
medulla oblongata	UBERON:0001896	39.48	gold quality
superior vestibular nucleus	UBERON:0007227	39.47	gold quality
cardia of stomach	UBERON:0001162	39.46	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.04

HPA expression

RNA tissue specificity: Group enriched

38 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Cerebellum	tissue	10.8
Olfactory bulb	tissue	10.7
Superior colliculi	tissue	9.4
Spinal cord	tissue	9.2
Cerebral cortex	tissue	8.9
Insular cortex	tissue	8.9
Amygdala	tissue	8.6
Basal ganglia	tissue	8.2
Retrosplenial cortex	tissue	8.1
Retrosplenial and cingulate cortex	tissue	7.9
Temporal cortex	tissue	7.9
Hippocampal formation	tissue	7.8
Entorhinal cortex	tissue	7.8
Corpus callosum	tissue	7.7
Ventral forebrain	tissue	7.3
Prefrontal cortex	tissue	7.2
Occipital cortex	tissue	7.0
Motor cortex	tissue	6.6
Putamen	tissue	6.6
Periaqueductal gray	tissue	6.5
Septum	tissue	6.5
Somatosensory cortex	tissue	6.2
Substantia nigra	tissue	5.8
Medulla oblongata	tissue	5.5
Hypothalamus	tissue	5.5
Placenta	tissue	5.2
Midbrain	tissue	5.0
Thalamus	tissue	4.3
Pons	tissue	4.2
Liver	tissue	3.1
Frontal cortex	tissue	0.3
Caudate putamen	tissue	0.3
Lymph node	tissue	0.2
Kidney	tissue	0.2
Duodenum	tissue	0.1
Thymus	tissue	0.1
Tonsil	tissue	0.1
Appendix	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 8; highest nTPM — Dorsal spinal cord (9.2), White matter (7.7), Subiculum (7.2), Ventral spinal cord (6.7), Ventral hippocampus (6.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PTMA

miRNA regulators (miRDB)

Targeting IDO2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 55 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-4441	99.49	66.56	3216

Functional genomics

gnomAD constraint: pLI 1.89e-05, LOEUF 1.26, missense Z -0.84 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000502986 — one region, missense o/e 1.11.

Literature-anchored findings (GeneRIF, showing 37)

• This article describes the evolutionary relationships between the INDO and INDOL1 genes. The INDOL1 protein has a distinct expression pattern compared to INDO and both have the ability to catabolise tryptophan. (PMID:17499941)
• IDO2 encodes a novel IDO-related tryptophan catabolic enzyme that is preferentially inhibited by D-1-methyl-tryptophan (D-1MT). IDO2 may have a distinct role in immune tolerance. Two common human genetic polymorphisms ablate IDO2 enzyme activity. (PMID:17671174)
• First study to report IDO2 expression in pancreatic ductal adenocarcinoma indicating that IDO2 genetic polymorphisms do not negate interferon-gamma-inducible protein expression. (PMID:19476837)
• High activity of indoleamine 2,3 dioxygenase enzyme predicts disease severity and case fatality in bacteremic patients. (PMID:19487973)
• The pro-apoptotic activity of indoleamine 2, 3-dioxygenase is responsible for its transcriptional regulation and the modulation of its pro-apoptotic activity during death receptor activation in melanoma cells. (PMID:19799997)
• Tryptophan supplementation was able to completely restore hepatitis b virus replication in IFN-gamma- but not IFN-alpha-treated cells, which strongly argues that IDO is the primary mediator of IFN-gamma-elicited antiviral response in human hepatocytes. (PMID:21084489)
• Data show that IDO2-specific T cells are cytotoxic effector cells that recognize and kill tumor cells. (PMID:21406395)
• Purification and kinetic characterization of human indoleamine 2,3-dioxygenases 1 and 2 (IDO1 and IDO2) and discovery of selective IDO1 inhibitors. (PMID:21835273)
• Indoleamine2,3-dioxygenase and tryptophanyl-tRNA synthetase may play critical roles in the immune pathogenesis of chronic kidney disease. (PMID:23651343)
• The IDO2 is now known to catalyze the first and rate-limiting step in the catabolism of tryptophan along a relative newcomer to the kynurenine pathway field. (PMID:24105077)
• IDO2 is expressed in both mDCs and plasmacytoid DCs and is not modulated by PGE2. IDO2 expression is constitutively, stably expressed in steady-state conditions and may contribute to the homeostatic tolerogenic capacity of DCs. (PMID:24391212)
• Multiple-scattering (MS) analysis of EXAFS data on met-indoleamine 2,3-dioxygenase-2 (IDO2) and analysis of XANES have provided the first direct structural information about the axial donor ligands of the iron center for this recently discovered protein. (PMID:24858687)
• Human indoleamine 2,3-dioxygenase-2 has substrate specificity and inhibition characteristics distinct from those of indoleamine 2,3-dioxygenase-1 (PMID:24875753)
• These results demonstrate that IDO2 plays a novel role as a negative regulator of IDO1 by competing for heme-binding with IDO1. (PMID:25394548)
• functional importance of IDO enzymes in human Crohn’s disease (PMID:25541686)
• High IDO2 expression is associated with cervical cancer. (PMID:27106797)
• High IDO2 expression is associated with Colorectal Cancer. (PMID:27578919)
• This study demonstrated that IDO2 rs10109853 and rs4503083 polymorphisms are not associated with MS risk, age at onset and disease progression in Italian MS patients. (PMID:28477703)
• Data suggest a strong association between the Indoleamine-2,3-Dioxygenase-2 (IDO2) inactivating Y359Stop single nucleotide polymorphism and an increased risk of familial pancreatic cancers when compared with the control group. (PMID:29426021)
• The results of this study provide genetic support for IDO2 as a contributing factor in PDAC development and argue that IDO2 genotype analysis has the immediate potential to influence the PDAC care decision-making process through stratification of those patients who stand to benefit from adjuvant radiotherapy (PMID:30266763)
• IDO expression correlates with intra-tumoral neutrophils infiltration and prognosis in the hepatocellular carcinoma patients. (PMID:30843276)
• Genetic Polymorphisms Affecting IDO1 or IDO2 Activity Differently Associate With Aspergillosis in Humans. (PMID:31134053)
• Elevated expression of IDO2 is associated with Chemoresistance in breast cancer. (PMID:31844921)
• Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on gammadelta T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells. (PMID:32384638)
• Indoleamine 2,3-Dioxygenase 2 Immunohistochemical Expression in Resected Human Non-small Cell Lung Cancer: A Potential New Prognostic Tool. (PMID:32536910)
• High PD-L1/IDO-2 and PD-L2/IDO-1 Co-Expression Levels Are Associated with Worse Overall Survival in Resected Non-Small Cell Lung Cancer Patients. (PMID:33671892)
• Methylene blue and ascorbate interfere with the accurate determination of the kinetic properties of IDO2. (PMID:33686747)
• IDO2 rs10109853 polymorphism affects the susceptibility to multiple myeloma. (PMID:33709342)
• Investigating the Role of Indoleamine 2,3-Dioxygenase in Acute Myeloid Leukemia: A Systematic Review. (PMID:33777052)
• Indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2 activity and severe course of COVID-19. (PMID:34859884)
• Single-nucleotide polymorphisms and activities of indoleamine 2,3-dioxygenase isoforms, IDO1 and IDO2, in tuberculosis patients. (PMID:35045867)
• Heterozygote Advantage of the Type II Deiodinase Thr92Ala Polymorphism on Intrahospital Mortality of COVID-19. (PMID:35137147)
• Indoleamine 2,3-dioxygenase 2 immunohistochemical expression in medullary thyroid carcinoma: implications in prognosis and immunomodulatory effects. (PMID:36319978)
• Regulation of IDO2 by the Aryl Hydrocarbon Receptor (AhR) in Breast Cancer. (PMID:37408267)
• Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARS-CoV-2 infection. (PMID:37506544)
• Membrane Localization and Phosphorylation of Indoleamine 2,3-Dioxygenase 2 (IDO2) in A549 Human Lung Adenocarcinoma Cells: First Steps in Exploring Its Signaling Function. (PMID:38003426)
• Marked IDO2 expression and activity related to autophagy and apoptosis in brain tissue of fatal tuberculous meningitis. (PMID:38460493)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ido2	ENSMUSG00000031549
rattus_norvegicus	Ido2	ENSRNOG00000025365

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2142489) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 6 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased susceptibility to type IV hypersensitivity reaction	2
abnormal regulatory T cell physiology	1
decreased tumor necrosis factor secretion	1
decreased interferon-gamma secretion	1
decreased interleukin-6 secretion	1
abnormal chemokine secretion	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Haliotis diversicolor	Q01966	87.3%	Diamond
Haliotis madaka	P51537	87.0%	Diamond
Aspergillus terreus NIH2624	Q0CG33	54.4%	Diamond
Aspergillus nanangensis	A0A6G9KIF9	46.9%	Diamond
Penicillium citrinum	P0DUR8	46.9%	Diamond
Fusarium equiseti	A0A823AAW6	37.8%	Diamond
Saccharomyces cerevisiae S288C	P47125	35.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LINC02866	ncRNA	105379385
IDO1	protein-coding	3620
TCIM	protein-coding	56892
SIRLNT	ncRNA	112543493
ZMAT4	protein-coding	79698
ADAM2	protein-coding	2515
ADAM18	protein-coding	8749

Protein

Protein identifiers

Indoleamine 2,3-dioxygenase 2 — Q6ZQW0 (reviewed: Q6ZQW0)

Alternative names: Indoleamine 2,3-dioxygenase-like protein 1, Indoleamine-pyrrole 2,3-dioxygenase-like protein 1

All UniProt accessions (1): Q6ZQW0

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the first and rate limiting step of the catabolism of the essential amino acid tryptophan along the kynurenine pathway. Involved in immune regulation. May not play a significant role in tryptophan-related tumoral resistance.

Tissue specificity. Detected in liver, small intestine, spleen, placenta, thymus, lung, brain, kidney, and colon. Also expressed at low level in testis and thyroid. Not expressed in the majority of human tumor samples (>99%).

Activity regulation. Activity is inhibited by D-1MT (1-methyl-D-tryptophan) and MTH-trp (methylthiohydantoin-DL-tryptophan) but not L-1MT (1-methyl-L-tryptophan).

Cofactor. Binds 1 heme group per subunit.

Pathway. Amino-acid degradation; L-tryptophan degradation via kynurenine pathway; L-kynurenine from L-tryptophan: step 1/2.

Polymorphism. The variant Trp-248 (p.R248W) drastically reduces the enzymatic activity. The Del359-420 variant (p.Y359X) generates a truncated, enzymatically inactive protein. The high prevalence of these polymorphic alleles results in a non-functional IDO2 enzyme in up to 50% of Caucasians.

Miscellaneous. IDO1 and IDO2 are 2 distinct enzymes which catalyze the same reaction. IDO2 affinity for tryptophan is much lower than that of IDO1. 50 % of Caucasians harbor polymorphisms which abolish IDO2 enzymatic activity. IDO2 is expressed in human tumors in an inactive form: tryptophan degradation is entirely provided by IDO1 in these cells. IDO2 may play a role as a negative regulator of IDO1 by competing for heme-binding with IDO1. Low efficiency IDO2 enzymes have been conserved throughout vertebrate evolution, whereas higher efficiency IDO1 enzymes are dispensable in many lower vertebrate lineages. IDO1 may have arisen by gene duplication of a more ancient proto-IDO gene before the divergence of marsupial and eutherian (placental) mammals.

Similarity. Belongs to the indoleamine 2,3-dioxygenase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6ZQW0-1	1	yes
Q6ZQW0-2	2

RefSeq proteins (2): NP_001382135, NP_919270* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000898	Indolamine_dOase	Family
IPR037217	Trp/Indoleamine_2_3_dOase-like	Homologous_superfamily

Pfam: PF01231

Enzyme classification (BRENDA)

• EC 1.13.11.11 — tryptophan 2,3-dioxygenase (BRENDA: 16 organisms, 15 substrates, 146 inhibitors, 17 Km, 8 kcat entries)
• EC 1.13.11.52 — indoleamine 2,3-dioxygenase (BRENDA: 49 organisms, 208 substrates, 831 inhibitors, 203 Km, 109 kcat entries)

Substrate kinetics (BRENDA)

23 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-TRYPTOPHAN	0.0007–62.4	96
D-TRYPTOPHAN	0.0019–16	27
L-TRYPTOPHAN	0.02–1.531	13
L-TRP	0.02–133	12
5-HYDROXY-L-TRYPTOPHAN	0.017–0.68	10
O2	0.037–119	10
5-FLUORO-DL-TRYPTOPHAN	0.006–100	6
5-METHYL-DL-TRYPTOPHAN	0.088–1.57	6
6-METHYL-DL-TRYPTOPHAN	0.056–3.457	5
D-TRP	0.3–5.2	5
6-FLUORO-DL-TRYPTOPHAN	0.186–186	4
1-METHYL-L-TRYPTOPHAN	0.062–0.696	3
1-METHYL-D-TRYPTOPHAN	0.66–0.747	2
5-FLUORO-TRYPTOPHAN	0.006–0.36	2
5-METHOXY-DL-TRYPTOPHAN	0.113–0.547	2

Catalyzed reactions (Rhea)

• L-tryptophan + O2 = N-formyl-L-kynurenine (RHEA:24536)

UniProt features (6 total): splice variant 2, sequence variant 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

11 structures by resolution:

PDB	Title	Method	Resolution (Å)
9UYY	Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) complexed with L-Trp	X-RAY DIFFRACTION	2.25
9UZ1	Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) H143Y mutant complexed …	X-RAY DIFFRACTION	2.35
9UYZ	Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) complexed with 5-HT	X-RAY DIFFRACTION	2.45
9UZ0	Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) as resting state	X-RAY DIFFRACTION	2.45
9UZ3	Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) complexed with D-Trp	X-RAY DIFFRACTION	2.5
9UZ4	Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) complexed with …	X-RAY DIFFRACTION	2.5
9UZ5	Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) complexed with …	X-RAY DIFFRACTION	2.5
21OO	Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) H143Y mutant complexed …	X-RAY DIFFRACTION	2.55
9UZ2	Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) complexed with Cyanide ion	X-RAY DIFFRACTION	2.55
21OK	Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) H143Y mutant complexed …	X-RAY DIFFRACTION	2.6
21OM	Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) complexed with …	X-RAY DIFFRACTION	2.68

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZQW0-F1	93.25	0.87

Human Protein Atlas

Protein class: Metabolic proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1)

Position	Role
347	heme

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-71240	Tryptophan catabolism	curated
R-HSA-1430728	Metabolism	—
R-HSA-71291	Metabolism of amino acids and derivatives	—

MSigDB gene sets: 113 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, REACTOME_TRYPTOPHAN_CATABOLISM, GCAAGGA_MIR502, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_NADPLUS_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_INDOLE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS

GO Biological Process (3): immune system process (GO:0002376), ‘de novo’ NAD+ biosynthetic process from L-tryptophan (GO:0034354), L-tryptophan catabolic process (GO:0006569)

GO Molecular Function (6): L-tryptophan 2,3-dioxygenase activity (GO:0004833), heme binding (GO:0020037), indoleamine 2,3-dioxygenase activity (GO:0033754), metal ion binding (GO:0046872), oxidoreductase activity (GO:0016491), dioxygenase activity (GO:0051213)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

17 GO namespaces:

Category	Terms
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen	2
cellular anatomical structure	2
biological_process	1
aromatic amino acid metabolic process	1
NAD+ biosynthetic process	1
indole-containing compound metabolic process	1
proteinogenic amino acid metabolic process	1
amino acid catabolic process	1
aromatic amino acid catabolic process	1
indole-containing compound catabolic process	1
proteinogenic amino acid catabolic process	1
tetrapyrrole binding	1
cation binding	1
catalytic activity	1
oxidoreductase activity	1
intracellular anatomical structure	1
cytoplasm	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 12 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
indoleamine 2,3-dioxygenase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,788 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IDO2	TDO2	P48775	953
IDO2	IFNG	P01579	892
IDO2	FOXP3	Q9BZS1	829
IDO2	CD4	P01730	821
IDO2	CTLA4	P16410	820
IDO2	TNFRSF18	Q9Y5U5	807
IDO2	TNFSF18	Q9UNG2	803
IDO2	CD80	P33681	795
IDO2	KYNU	Q16719	790
IDO2	KMO	O15229	790
IDO2	IL10	P22301	776
IDO2	TNF	P01375	771
IDO2	CD274	Q9NZQ7	754
IDO2	IL2	P01585	753
IDO2	IL6	P05231	747

IntAct

Human interaction partners of IDO2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
ATF1	association	0.350	1

BioGRID (16 interactions; top human partners by supporting records): ATF1 (Affinity Capture-MS; 2 records), DPP8 (Affinity Capture-MS; 2 records), EME1 (Affinity Capture-MS; 2 records), KLF12 (Affinity Capture-MS; 2 records), NRN1 (Affinity Capture-MS; 2 records), BANP (Two-hybrid), ERICH5 (Affinity Capture-MS), FAM171A2 (Affinity Capture-MS), LZTS1 (Two-hybrid), SMARCA1 (Affinity Capture-MS), ULBP2 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for IDO2: 78 ClinVar records (1 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

78 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	61
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
4888407	GRCh38/hg38 8p12-q11.1(chr8:35340961-46330497)x3	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore IDO2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 1,353):

Position(s)	Effect	Δscore	Sites
8:39985477	acceptor_gain	1.0000
8:40013708	donor_gain	1.0000
8:40013714–40013715	donor_loss	1.0000	5
8:40015245–40015246	acceptor_loss	1.0000	3
8:39963601	acceptor_gain	0.9900
8:39989839–39989840	donor_loss	0.9900	6
8:39991083	donor_gain	0.9900
8:40013563–40013564	acceptor_loss	0.9900	3
8:40015245	acceptor_loss	0.9900	2
8:39979187–39979188	donor_loss	0.9800	6

AlphaMissense

411 missense substitutions predicted likely pathogenic (of 2,755 scored), across 142 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D291	8	0.883	0.924
E188	7	0.884	0.958
F40	7	0.878	0.981
F180	7	0.875	0.969
W56	7	0.823	0.956
W254	7	0.804	0.941
N150	7	0.792	0.938
W109	7	0.759	0.828
D145	7	0.728	0.774
H317	7	0.683	0.841
F243	6	0.828	0.932
F320	6	0.806	0.938
M313	6	0.775	0.835
Q283	6	0.764	0.925
H360	6	0.740	0.862
M309	6	0.720	0.806
S284	5	0.919	0.978
F305	5	0.872	0.943
F403	5	0.869	0.921
S280	5	0.868	0.967

HPA cancer prognostics

RNA cancer specificity: Not detected

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (validation)	favorable	0.000196

Disease associations

OMIM: gene MIM:612129 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST012310_22	Schizophrenia x sex interaction	2e-6
GCST012311_19	Schizophrenia x sex interaction	5e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3627587 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 8,583 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

2 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL3545369	EPACADOSTAT	3	6,316
CHEMBL1475252	TENATOPRAZOLE	2	2,267

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Dioxygenases

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
example 184 [WO2014186035]	Inhibition	6.0	pIC50
tryptanthrin 5i	Inhibition	5.74	pIC50

Binding affinities (BindingDB)

137 measured of 210 human assays (210 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL5091825	IC50	2.2 nM
CHEMBL4514196	IC50	10 nM
CHEMBL4791168	IC50	13 nM
CHEMBL4588805	IC50	20 nM
CHEMBL4437046	IC50	20 nM
Methyl 3-chloro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazoline-8-carboxylate	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
N-(3-Chloro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-8-yl)acetamide	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
3-Chloro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazoline-8-carboxamide	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
1,3-Difluoro-8-nitroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
3-Fluoro-8-(methylsulfonyl)indolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
8-Fluoro-3-((4-methylpiperazin-1-yl)methyl)indolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
3-Amino-8-nitroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
tert-Butyl (8-nitro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-3-yl)carbamate	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
1,3-Dichloro-N-methyl-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazoline-8-carboxamide	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
1,3-Dichloro-6,12-dioxoindolo[2,1-b]quinazoline-8-carboxamide	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
1,3-Dichloro-N,N-dimethyl-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazoline-8-carboxamide	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
4-Bromo-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazoline-8-carbonitrile	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
8-(Benzylthio)-3-fluoroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
3-Fluoro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazoline-8-sulfonamide	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
3-Fluoro-4-methyl-8-nitroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
3-Fluoro-6-hydroxy-12-oxo-5,5a,6,12-tetrahydroindolo[2,1-b]quinazoline-8-carbonitrile	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
1,3-Difluoro-6-hydroxy-8-nitro-5a,6-dihydroindolo[2,1-b]quinazolin-12(5H)-one	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
4-bromo-3-fluoro-8-nitroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
4-Chloro-8-nitroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
1-Chloro-8-nitroindolo[2,1-b]quinazolin-12(5H)-one	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
1-fluoro-4-methyl-8-nitroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
4-Fluoro-8-nitroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
4-Bromo-8-nitroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
4-Bromo-8-fluoroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
4-Bromo-2-fluoro-8-nitroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
Synthesis of 4-bromo-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazoline-8-carbonitrile	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
2-Fluoro-4-methyl-8-nitroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
1,3-Dichloro-8-nitroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
3-Methoxy-9-nitropyrido[3’,4’:4,5]pyrimido[1,2-a]indole-5,11-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
8-Nitroindolo[2,1-b]quinazolin-12(6H)-one	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
3-bromo-8-nitroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
3-fluoro-8-methylsulfonyl-6-nitroso-5H-indolo[2,1-b]quinazolin-12-one	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
N-(2-aminoethyl)-3-chloro-6-nitroso-12-oxo-5H-indolo[2,1-b]quinazoline-8-carboxamide	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
N-(3-chloro-6,12-dioxoindolo[2,1-b]quinazolin-8-yl)-3-(3-methyldiazirin-3-yl)propanamide	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
3-chloro-6,12-dioxoindolo[2,1-b]quinazoline-8-sulfonamide	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
tert-butyl N-[2-[(3-chloro-6,12-dioxoindolo[2,1-b]quinazoline-8-carbonyl)amino]ethyl]carbamate	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
8-benzylsulfanyl-3-chloroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
3-fluoro-12-oxo-6H-indolo[2,1-b]quinazoline-8-carboxamide	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
3-fluoro-8-methylsulfonyl-6H-indolo[2,1-b]quinazolin-12-one	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
N-(1,3-dichloro-6,12-dioxoindolo[2,1-b]quinazolin-8-yl)methanesulfonamide	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
Synthesis of 8-fluoro-3-(1H-imidazol-4-yl)indolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
Synthesis of 3-(aminomethyl)-8-fluoroindolo[2,1-b]quinazoline-6,12-dione Hydrochloride Salt	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
Synthesis of benzyl (Z)-((8-fluoro-6-(methoxyimino)-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-3-yl)methyl)carbamate	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
Synthesis of (Z)—N-((8-fluoro-6-(methoxyimino)-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-3-yl)methyl)acetamide	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF
Synthesis of 1-(aminomethyl)-8-fluoroindolo[2,1-b]quinazoline-6,12-dione	IC50	20 nM	US-20250171452: TRYPTANTHRIN DERIVATIVES AND USES THEREOF

ChEMBL bioactivities

59 potent at pChembl≥5 of 129 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.95	IC50	112	nM	CHEMBL5219888
6.87	IC50	134	nM	CHEMBL5220224
6.84	IC50	144	nM	CHEMBL5091825
6.55	IC50	280	nM	CHEMBL4472697
6.51	IC50	310	nM	CHEMBL4791168
6.44	IC50	362	nM	CHEMBL5085580
6.41	IC50	387	nM	CHEMBL5221035
6.35	IC50	450	nM	CHEMBL432537
6.35	IC50	446	nM	CHEMBL432537
6.31	IC50	490	nM	CHEMBL4514196
6.24	IC50	575	nM	CHEMBL5221037
6.23	IC50	590	nM	CHEMBL4436582
6.20	IC50	630	nM	EPACADOSTAT
6.16	IC50	689	nM	CHEMBL5082481
6.15	IC50	710	nM	EPACADOSTAT
6.14	IC50	726	nM	CHEMBL5090441
6.10	IC50	794	nM	CHEMBL5092513
6.08	IC50	830	nM	CHEMBL5091241
6.06	IC50	865	nM	CHEMBL5091415
6.03	IC50	930	nM	CHEMBL5091243
6.02	IC50	958	nM	CHEMBL5093816
6.02	IC50	947	nM	CHEMBL5091590
6.02	IC50	958	nM	CHEMBL5084150
6.01	Ki	970	nM	CHEMBL432537
5.97	IC50	1081	nM	CHEMBL5078912
5.93	IC50	1174	nM	CHEMBL5078101
5.93	IC50	1171	nM	CHEMBL5088729
5.92	IC50	1200	nM	CHEMBL1098875
5.91	IC50	1230	nM	CHEMBL1098875
5.75	IC50	1800	nM	CHEMBL432537
5.75	IC50	1800	nM	TENATOPRAZOLE
5.73	IC50	1870	nM	CHEMBL432537
5.73	IC50	1874	nM	CHEMBL5084767
5.71	Ki	1960	nM	CHEMBL4436480
5.50	IC50	3200	nM	CHEMBL72165
5.49	IC50	3220	nM	CHEMBL72165
5.46	Ki	3500	nM	CHEMBL1098875
5.46	Ki	3510	nM	CHEMBL1098875
5.45	IC50	3580	nM	CHEMBL4436480
5.42	IC50	3810	nM	CHEMBL4452150
5.37	Ki	4320	nM	CHEMBL4452150
5.30	IC50	5000	nM	TRYPTANTHRIN
5.30	IC50	5010	nM	TRYPTANTHRIN
5.25	Ki	5600	nM	CHEMBL72165
5.25	Ki	5620	nM	CHEMBL72165
5.21	Ki	6110	nM	CHEMBL4577825
5.20	Ki	6320	nM	CHEMBL4437046
5.12	IC50	7600	nM	CHEMBL1098875
5.12	IC50	7680	nM	CHEMBL1098875
5.09	IC50	8200	nM	CHEMBL3087009

PubChem BioAssay actives

48 with measured affinity, of 277 total; 35 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[[1-[2-[[4-[N’-[(3-bromophenyl)methyl]-N-hydroxycarbamimidoyl]-1,2,5-oxadiazol-3-yl]amino]ethyl]triazol-4-yl]methyl]pyridine-2-carboxamide	1916992: Inhibition of human IDO2	ic50	0.1120	uM
N-[[1-[2-[[4-[N’-(3-bromo-4-fluorophenyl)-N-hydroxycarbamimidoyl]-1,2,5-oxadiazol-3-yl]amino]ethyl]triazol-4-yl]methyl]-1H-pyrrole-2-carboxamide	1916992: Inhibition of human IDO2	ic50	0.1340	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-(2-hydroxyethoxymethyl)triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	0.1440	uM
N’-(3-bromo-4-fluorophenyl)-4-[2-[[ethoxy(ethyl)phosphoryl]amino]ethylamino]-N-hydroxy-1,2,5-oxadiazole-3-carboximidamide	1609232: Inhibition of N-terminal His-tagged human IDO2 expressed in Escherichia coli expression system	ic50	0.2800	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[3-[[methoxy(methyl)phosphoryl]amino]propylamino]-1,2,5-oxadiazole-3-carboximidamide	1728731: Inhibition of N-terminal 6His-tagged recombinant human IDO2 (15 to 420 residues) expressed in Escherichia coli using L-Trp as substrate by UV absorbance method	ic50	0.3100	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-(1-hydroxyethyl)triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	0.3620	uM
N-[[1-[2-[[4-[N’-(3-bromo-4-fluorophenyl)-N-hydroxycarbamimidoyl]-1,2,5-oxadiazol-3-yl]amino]ethyl]triazol-4-yl]methyl]pyridine-2-carboxamide	1916992: Inhibition of human IDO2	ic50	0.3870	uM
8-nitroindolo[2,1-b]quinazoline-6,12-dione	1332708: Inhibition of recombinant human IDO2 expressed in human U87MG cells assessed as reduction in kynurenine formation using L-tryptophan as substrate after 6 hrs by spectrophotometry	ic50	0.4500	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[[methoxy(methyl)phosphoryl]amino]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1609232: Inhibition of N-terminal His-tagged human IDO2 expressed in Escherichia coli expression system	ic50	0.4900	uM
N-[[1-[2-[[4-[N’-(3-bromophenyl)-N-hydroxycarbamimidoyl]-1,2,5-oxadiazol-3-yl]amino]ethyl]triazol-4-yl]methyl]pyridine-2-carboxamide	1916992: Inhibition of human IDO2	ic50	0.5750	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[4-[[methoxy(methyl)phosphoryl]amino]butylamino]-1,2,5-oxadiazole-3-carboximidamide	1609232: Inhibition of N-terminal His-tagged human IDO2 expressed in Escherichia coli expression system	ic50	0.5900	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole-3-carboximidamide	2032194: Inhibition of IDO2 (unknown origin) using D-Trp as substrate incubated for 1 hr	ic50	0.6300	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-(2-hydroxy-4-methylpentan-2-yl)triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	0.6890	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-(2-hydroxypropan-2-yl)triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	0.7260	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-(hydroxymethyl)triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	0.7940	uM
N’-(3-bromo-4-fluorophenyl)-4-[2-(4-butyltriazol-1-yl)ethylamino]-N-hydroxy-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	0.8300	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-(1-hydroxycyclohexyl)triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	0.8650	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-[1-(2-hydroxyethoxy)ethyl]triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	0.9300	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-(1-hydroxypropyl)triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	0.9470	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-(2-hydroxybutan-2-yl)triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	0.9580	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-(3-hydroxypropyl)triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	0.9580	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-(4-hydroxybutyl)triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	1.0810	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-[2-(2-hydroxyethoxy)propan-2-yl]triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	1.1710	uM
N’-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-[4-(2-hydroxyethyl)triazol-1-yl]ethylamino]-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	1.1740	uM
8-fluoroindolo[2,1-b]quinazoline-6,12-dione	1332708: Inhibition of recombinant human IDO2 expressed in human U87MG cells assessed as reduction in kynurenine formation using L-tryptophan as substrate after 6 hrs by spectrophotometry	ic50	1.2000	uM
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine	1917028: Inhibition of IDO2 (unknown origin)	ic50	1.8000	uM
N’-(3-bromo-4-fluorophenyl)-4-[2-(4-tert-butyltriazol-1-yl)ethylamino]-N-hydroxy-1,2,5-oxadiazole-3-carboximidamide	1833933: Inhibition of IDO2 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay	ic50	1.8740	uM
8-fluoro-2-(piperazin-1-ylmethyl)indolo[2,1-b]quinazoline-6,12-dione	1558441: Uncompetitive inhibition of C-terminal His6-tagged human IDO2 (14 to 420 residues) expressed in Escherichia coli BL21 (DE3) assessed as inhibition constant using varying concentration of L-tryptophan as substrate by Dixon plot analysis	ki	1.9600	uM
8-bromoindolo[2,1-b]quinazoline-6,12-dione	1332708: Inhibition of recombinant human IDO2 expressed in human U87MG cells assessed as reduction in kynurenine formation using L-tryptophan as substrate after 6 hrs by spectrophotometry	ic50	3.2000	uM
2-[(dimethylamino)methyl]-8-fluoroindolo[2,1-b]quinazoline-6,12-dione	1558435: Inhibition of human IDO2 transfected in human U87MG cells assessed as reduction in kynurenine production using L-tryptophan as substrate incubated with for 6 hrs	ic50	3.8100	uM
indolo[2,1-b]quinazoline-6,12-dione	1332708: Inhibition of recombinant human IDO2 expressed in human U87MG cells assessed as reduction in kynurenine formation using L-tryptophan as substrate after 6 hrs by spectrophotometry	ic50	5.0000	uM
tert-butyl 4-[(8-fluoro-6,12-dioxoindolo[2,1-b]quinazolin-2-yl)methyl]piperazine-1-carboxylate	1558441: Uncompetitive inhibition of C-terminal His6-tagged human IDO2 (14 to 420 residues) expressed in Escherichia coli BL21 (DE3) assessed as inhibition constant using varying concentration of L-tryptophan as substrate by Dixon plot analysis	ki	6.1100	uM
8-fluoro-2-[(4-methylpiperazin-1-yl)methyl]indolo[2,1-b]quinazoline-6,12-dione	1558440: Mixed competitive inhibition of C-terminal His6-tagged human IDO2 (14 to 420 residues) expressed in Escherichia coli BL21 (DE3) assessed as inhibition constant using varying concentration of L-tryptophan as substrate by Dixon plot analysis	ki	6.3200	uM
2,8-difluoroindolo[2,1-b]quinazoline-6,12-dione	1332708: Inhibition of recombinant human IDO2 expressed in human U87MG cells assessed as reduction in kynurenine formation using L-tryptophan as substrate after 6 hrs by spectrophotometry	ic50	8.2000	uM
2-[(4-methylpiperazin-1-yl)methyl]indolo[2,1-b]quinazoline-6,12-dione	1558442: Mixed uncompetitive inhibition of C-terminal His6-tagged human IDO2 (14 to 420 residues) expressed in Escherichia coli BL21 (DE3) assessed as inhibition constant using varying concentration of L-tryptophan as substrate by Dixon plot analysis	ki	8.8500	uM

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	2
Lipopolysaccharides	affects cotreatment, increases expression, affects response to substance	2
Tetrachlorodibenzodioxin	decreases reaction, increases expression	2
salinomycin	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
indeno(1,2,3-cd)pyrene	increases expression	1
3’-methoxy-4’-nitroflavone	decreases reaction, increases expression	1
abrine	increases expression	1
CL 075	increases expression	1
(+)-JQ1 compound	decreases expression	1
Poly I-C	increases expression	1
Valproic Acid	increases methylation	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1
Permethrin	increases expression	1

ChEMBL screening assays

46 unique, capped per target: 46 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3630806	Binding	Inhibition of human IDO2	Challenges and Opportunities in the Discovery of New Therapeutics Targeting the Kynurenine Pathway. — *J Med Chem*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for IDO2 across ~30M SureChEMBL compounds — explore on Sugi Predict.