TDO2

Summary

TDO2 (tryptophan 2,3-dioxygenase, HGNC:11708) is a protein-coding gene on chromosome 4q32.1, encoding Tryptophan 2,3-dioxygenase (P48775). Heme-dependent dioxygenase that catalyzes the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring and converts L-tryptophan to N-formyl-L-kynurenine.

This gene encodes a heme enzyme that plays a critical role in tryptophan metabolism by catalyzing the first and rate-limiting step of the kynurenine pathway. Increased activity of the encoded protein and subsequent kynurenine production may also play a role in cancer through the suppression of antitumor immune responses, and single nucleotide polymorphisms in this gene may be associated with autism.

Source: NCBI Gene 6999 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial hypertryptophanemia (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 142 total
• Phenotypes (HPO): 26
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005651

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11708
Approved symbol	TDO2
Name	tryptophan 2,3-dioxygenase
Location	4q32.1
Locus type	gene with protein product
Status	Approved
Aliases	TDO, TPH2
Ensembl gene	ENSG00000151790
Ensembl biotype	protein_coding
OMIM	191070
Entrez	6999

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000503634, ENST00000506072, ENST00000506181, ENST00000507590, ENST00000509738, ENST00000510293, ENST00000512584, ENST00000536354, ENST00000874684, ENST00000874685, ENST00000874686, ENST00000874687, ENST00000874688, ENST00000874689

RefSeq mRNA: 1 — MANE Select: NM_005651 NM_005651

CCDS: CCDS34086

Canonical transcript exons

ENST00000536354 — 12 exons

Exon	Start	End
ENSE00002023705	155919837	155920406
ENSE00002210100	155903696	155903793
ENSE00002237691	155910025	155910211
ENSE00003483253	155914323	155914434
ENSE00003530189	155911497	155911604
ENSE00003530647	155908887	155909014
ENSE00003533954	155904018	155904123
ENSE00003547271	155907722	155907792
ENSE00003549508	155918149	155918239
ENSE00003579395	155915855	155915912
ENSE00003644471	155917395	155917474
ENSE00003683789	155905067	155905157

Expression profiles

Bgee: expression breadth ubiquitous, 127 present calls, max score 99.09.

FANTOM5 (CAGE): breadth broad, TPM avg 4.5084 / max 1705.7398, expressed in 560 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50220	3.5217	249
50219	0.7197	286
50218	0.2671	138

Top tissues by expression

133 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.09	gold quality
liver	UBERON:0002107	98.31	gold quality
vermiform appendix	UBERON:0001154	90.95	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.70	gold quality
duodenum	UBERON:0002114	76.54	gold quality
lymph node	UBERON:0000029	74.67	gold quality
pituitary gland	UBERON:0000007	73.47	gold quality
gall bladder	UBERON:0002110	72.35	gold quality
adenohypophysis	UBERON:0002196	70.35	gold quality
rectum	UBERON:0001052	69.90	gold quality
superior frontal gyrus	UBERON:0002661	68.95	gold quality
left adrenal gland	UBERON:0001234	67.33	gold quality
small intestine	UBERON:0002108	66.90	gold quality
smooth muscle tissue	UBERON:0001135	66.82	gold quality
primary visual cortex	UBERON:0002436	66.58	gold quality
adrenal tissue	UBERON:0018303	66.45	gold quality
adrenal gland	UBERON:0002369	66.37	gold quality
islet of Langerhans	UBERON:0000006	66.11	gold quality
right adrenal gland cortex	UBERON:0035827	66.09	gold quality
small intestine Peyer’s patch	UBERON:0003454	65.97	gold quality
endometrium	UBERON:0001295	65.74	gold quality
left adrenal gland cortex	UBERON:0035825	65.09	gold quality
prefrontal cortex	UBERON:0000451	64.77	gold quality
right adrenal gland	UBERON:0001233	64.74	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	64.59	gold quality
Brodmann (1909) area 9	UBERON:0013540	64.37	gold quality
frontal cortex	UBERON:0001870	63.45	gold quality
lung	UBERON:0002048	63.37	gold quality
placenta	UBERON:0001987	63.14	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	31.97
E-ANND-3	no	2.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, ESR1, FOXO1, GATA4, NR3C1, POU3F2, SMARCA1, YY1

miRNA regulators (miRDB)

37 targeting TDO2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-8062	99.88	68.43	995
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-6807-3P	99.15	69.23	1275
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-6074	98.89	69.64	2187
HSA-MIR-4742-3P	98.73	69.82	1803
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-6754-5P	98.60	65.54	1627

Literature-anchored findings (GeneRIF, showing 36)

• The activity and mRNA expression level of indoleamine 2,3-dioxygenase in term placentas were significantly lower in preeclampsia. Could cause dysregulation of inflammatory response intrinsic to normal pregnancy. (PMID:12634647)
• Polymorphism of tryptophan 2,3 dioxygenase gene is associated with autism. (PMID:14755447)
• We found that astrocytes, neurons, and microglia expressed IDO but only microglia were able to produce detectable amounts of quinolinic acid. However, astrocytes and neurons had the ability to catabolize quinolinic acid. (PMID:15390107)
• significant mechanistic differences exist across the heme dioxygenase family, and the data are discussed within this broader framework (PMID:18370401)
• The tyrosine 42 of recombinant human TDO is responsible for the cooperative binding of l-Trp by participating in the active site of the adjacent subunit. (PMID:19218188)
• TDO mediates antimicrobial and immunoregulatory effects. TDO-dependent inhibition of T-cell growth might be involved in the immunotolerance observed in vivo during allogeneic liver transplantation. (PMID:19637229)
• subtle differences between the TDO and IDO reactions (PMID:20361220)
• Studies indicate that the heme dioxygenases are differentiated by their ability to catalyze the oxidation of l-tryptophan to N-formylkynurenine. (PMID:21361337)
• The data suggest that TDO uses a ring-opening mechanism during N-formylkynurenine formation, rather than Criegee or dioxetane mechanisms as previously proposed. (PMID:21892828)
• Data suggest that T342 in hTDO has critical role in controlling substrate binding, substrate stereoselectivity, H-bonding interaction between enzyme and intermediates, and regulating the dynamics of protein structure. (PMID:22082147)
• Identification of 12 polymorphisms in the human TDO2 promoter region, 2 of them corresponding to previously unknown single-nucleotide polymorphisms and 3 of them located in putative glucocorticoid-responsive elements. (PMID:23558111)
• TDO is highly expressed in the brains of Alzheimer disease patients. (PMID:23630570)
• IL-1beta is suggested to stimulate tryptophan catabolism and production of IL-6 and IL-8 by increasing TDO expression in endometriosis. (PMID:24974860)
• Crystal tryptophan 2,3-dioxygenase structure revealed eight residues playing critical roles in L-tryptophan oxidation. (PMID:25066423)
• the potent antimicrobial as well as immunoregulatory effects of TDO were substantially impaired under hypoxic conditions that pathophysiologically occur in vivo. This might be detrimental for the appropriate host immune response towards relevant pathogens. (PMID:27563172)
• High TDO2 expression is associated with Colorectal Cancer. (PMID:27578919)
• Study demonstrated that n-butylidenephthalide (n-BP)functions by regulating the early part of the kynurenine pathway through the downregulation of tryptophan 2, 3-dioxygenase (TDO2), which decreases the downstream neurotoxic product, quinolinic acid (QA). Findings indicate a correlation between n-BP, TDO2, QA, calpain, and toxic fragment formation. (PMID:28223212)
• HOXC10 directly binds to the PD-L2 and TDO2 promoter regions thus stimulating proliferation, invasion and induction of immunosuppressive gene expression in glioma. (PMID:29676849)
• TDO2 overexpression was related to poor prognosis and associated with cancer cell proliferation and tumor stem cells in esophageal squamous cell carcinoma. (PMID:30134247)
• Tryptophan 2,3-Dioxygenase Expression Identified in Human Hepatocellular Carcinoma Cells and in Intratumoral Pericytes of Most Cancers. (PMID:31806639)
• Hypoxia Inducible Factor 1alpha Inhibits the Expression of Immunosuppressive Tryptophan-2,3-Dioxygenase in Glioblastoma. (PMID:31866995)
• Gene expression of indoleamine and tryptophan dioxygenases and three long non-coding RNAs in breast cancer. (PMID:32165090)
• Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn-AhR-AQP4 signaling pathway. (PMID:32296044)
• Different effects of tryptophan 2,3-dioxygenase inhibition on SK-Mel-28 and HCT-8 cancer cell lines. (PMID:32776284)
• Tryptophan 2, 3dioxygenase promotes proliferation, migration and invasion of ovarian cancer cells. (PMID:33846800)
• TDO2 knockdown inhibits colorectal cancer progression via TDO2-KYNU-AhR pathway. (PMID:34051337)
• TDO2 overexpression correlates with poor prognosis, cancer stemness, and resistance to cetuximab in bladder cancer. (PMID:34101386)
• TDO2 Was Downregulated in Hepatocellular Carcinoma and Inhibited Cell Proliferation by Upregulating the Expression of p21 and p27. (PMID:34423034)
• IDO1/TDO dual inhibitor RY103 targets Kyn-AhR pathway and exhibits preclinical efficacy on pancreatic cancer. (PMID:34520819)
• Stemness and immune evasion conferred by the TDO2-AHR pathway are associated with liver metastasis of colon cancer. (PMID:34714577)
• Immuno-Metabolic Modulation of Liver Oncogenesis by the Tryptophan Metabolism. (PMID:34943977)
• Tryptophan 2,3-dioxygenase 2 plays a key role in regulating the activation of fibroblast-like synoviocytes in autoimmune arthritis. (PMID:34969166)
• MiR-126-5p Promotes Tumor Cell Proliferation, Metastasis and Invasion by Targeting TDO2 in Hepatocellular Carcinoma. (PMID:35056756)
• Essential Roles of TDO2 in Gastric Cancer: TDO2 Is Associated with Cancer Progression, Patient Survival, PD-L1 Expression, and Cancer Stem Cells. (PMID:35679834)
• High levels of TDO2 in relation to pro-inflammatory cytokines in synovium and synovial fluid of patients with osteoarthritis. (PMID:35733134)
• Tryptophan degradation enzymes and Angiotensin (1-7) expression in human placenta. (PMID:35970080)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tdo2b	ENSDARG00000023176
danio_rerio	tdo2a	ENSDARG00000071429
mus_musculus	Tdo2	ENSMUSG00000028011
rattus_norvegicus	Tdo2	ENSRNOG00000011612
drosophila_melanogaster	v	FBGN0003965
caenorhabditis_elegans		WBGENE00016201

Protein

Protein identifiers

Tryptophan 2,3-dioxygenase — P48775 (reviewed: P48775)

Alternative names: Tryptamin 2,3-dioxygenase, Tryptophan oxygenase, Tryptophan pyrrolase, Tryptophanase

All UniProt accessions (3): P48775, D6RA50, D6RB68

UniProt curated annotations — full annotation on UniProt →

Function. Heme-dependent dioxygenase that catalyzes the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring and converts L-tryptophan to N-formyl-L-kynurenine. Catalyzes the oxidative cleavage of the indole moiety.

Subunit / interactions. Homotetramer. Dimer of dimers.

Disease relevance. Hypertryptophanemia (HYPTRP) [MIM:600627] An autosomal recessive condition characterized by persistent hypertryptophanemia and hyperserotoninemia. The disease is caused by variants affecting the gene represented in this entry.

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.

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

RefSeq proteins (1): NP_005642* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004981	Trp_2_3_dOase	Family
IPR037217	Trp/Indoleamine_2_3_dOase-like	Homologous_superfamily

Pfam: PF03301

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), 1 shown:

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

UniProt features (48 total): helix 28, mutagenesis site 9, binding site 4, turn 4, chain 1, strand 1, sequence variant 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
6PYZ	X-RAY DIFFRACTION	2.02
6UD5	X-RAY DIFFRACTION	2.05
8VTQ	X-RAY DIFFRACTION	2.05
8VUG	X-RAY DIFFRACTION	2.05
8W1H	X-RAY DIFFRACTION	2.1
9AT2	X-RAY DIFFRACTION	2.25
8VZV	X-RAY DIFFRACTION	2.29
7LU7	X-RAY DIFFRACTION	2.3
6PYY	X-RAY DIFFRACTION	2.4
5TIA	X-RAY DIFFRACTION	2.44
8W2K	X-RAY DIFFRACTION	2.45
5TI9	X-RAY DIFFRACTION	2.5
9EZJ	X-RAY DIFFRACTION	2.61
8R5Q	X-RAY DIFFRACTION	2.62
9B1Q	X-RAY DIFFRACTION	2.62
6A4I	X-RAY DIFFRACTION	2.65
9B17	X-RAY DIFFRACTION	2.65
4PW8	X-RAY DIFFRACTION	2.9
8QV7	X-RAY DIFFRACTION	2.93
8R5R	X-RAY DIFFRACTION	3.08
6VBN	X-RAY DIFFRACTION	3.18
7UI3	X-RAY DIFFRACTION	3.18

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48775-F1	90.63	0.82

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 (4): 72–76; 144; 328 (axial binding residue); 342

Mutagenesis-validated functional residues (9):

Position	Phenotype
140	reduces enzyme activity by 99%.
144	reduces enzyme activity by 99%.
151	reduces enzyme activity by 90%.
175	reduces enzyme activity.
328	abolishes enzyme activity.
42	reduces enzyme activity by 99%.
45	reduces enzyme activity by 99%.
72	abolishes enzyme activity.
76	abolishes enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

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

MSigDB gene sets: 339 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, MODULE_93, LI_CISPLATIN_RESISTANCE_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, chr4q32, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, REACTOME_TRYPTOPHAN_CATABOLISM, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (8): obsolete L-tryptophan catabolic process to L-kynurenine (GO:0019441), obsolete L-tryptophan catabolic process to acetyl-CoA (GO:0019442), response to ethanol (GO:0045471), protein homotetramerization (GO:0051289), response to cortisol (GO:0051414), response to nitroglycerin (GO:1904842), obsolete L-tryptophan metabolic process (GO:0006568), L-tryptophan catabolic process (GO:0006569)

GO Molecular Function (9): L-tryptophan 2,3-dioxygenase activity (GO:0004833), amino acid binding (GO:0016597), oxygen binding (GO:0019825), heme binding (GO:0020037), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), dioxygenase activity (GO:0051213)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to alcohol	2
binding	2
protein homooligomerization	1
protein tetramerization	1
response to glucocorticoid	1
response to ketone	1
response to nitrogen compound	1
response to oxygen-containing compound	1
aromatic amino acid catabolic process	1
indole-containing compound catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen	1
small molecule binding	1
tetrapyrrole binding	1
protein binding	1
cation binding	1
catalytic activity	1
oxidoreductase activity	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1594 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TDO2	IDO2	Q6ZQW0	956
TDO2	IDO1	P14902	907
TDO2	KMO	O15229	875
TDO2	KYNU	Q16719	874
TDO2	HAAO	P46952	835
TDO2	AFMID	Q63HM1	807
TDO2	TAT	P17735	791
TDO2	ACMSD	Q8TDX5	759
TDO2	QPRT	Q15274	737
TDO2	KYAT1	Q16773	712
TDO2	AADAT	Q8N5Z0	697
TDO2	PPOX	P50336	659
TDO2	KYAT3	Q6YP21	638
TDO2	HMBS	P08396	619
TDO2	TPH1	P17752	600

IntAct

116 interactions, top by confidence:

A	B	Type	Score
ASMTL	TDO2	psi-mi:“MI:0915”(physical association)	0.910
TDO2	ASMTL	psi-mi:“MI:0915”(physical association)	0.910
TDO2	SDCBP	psi-mi:“MI:0915”(physical association)	0.780
SDCBP	TDO2	psi-mi:“MI:0915”(physical association)	0.780
TDO2	TDO2	psi-mi:“MI:0915”(physical association)	0.740
DPM1	TDO2	psi-mi:“MI:0915”(physical association)	0.720
TDO2	ZFYVE26	psi-mi:“MI:0915”(physical association)	0.720
MOB1A	TDO2	psi-mi:“MI:0915”(physical association)	0.720
NGB	TDO2	psi-mi:“MI:0915”(physical association)	0.720
ZFYVE26	TDO2	psi-mi:“MI:0915”(physical association)	0.720
TDO2	NGB	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (43): TDO2 (Two-hybrid), TDO2 (Two-hybrid), TDO2 (Two-hybrid), TDO2 (Two-hybrid), ASMTL (Two-hybrid), DPM1 (Two-hybrid), ZFYVE26 (Two-hybrid), SDCBP2 (Two-hybrid), MOB1A (Two-hybrid), NGB (Two-hybrid), MOB3C (Two-hybrid), ASMTL (Two-hybrid), TDO2 (Two-hybrid), ASMTL (Affinity Capture-MS), TDO2 (Two-hybrid)

ESM2 similar proteins: A0JUV5, A0REX0, A4IT59, A7MBU6, A8GG83, A8X7X9, A9VHP7, B0RMW5, B1KJM2, B2SM13, B3MQP7, B3NVC6, B4H4U3, B4IDV8, B4JKK1, B4L629, B4M818, B4MSH7, B4PYW0, B4RUH2, O08739, O09178, O77457, P10759, P20351, P21643, P23109, P48775, P48776, Q01432, Q09474, Q17P71, Q1CVR6, Q24630, Q29I03, Q2KIQ5, Q2LD53, Q3V1D3, Q4UZJ5, Q55DB4

Diamond homologs: A0JUV5, A0KA02, A0REX0, A1SG03, A1V193, A1VRP1, A2S924, A3MHE1, A3N6H2, A3NS55, A4FH01, A4IT59, A4YND6, A5EQH6, A6W961, A7MBU6, A8GG83, A8X7X9, A9AGH1, A9B4J6, A9FU01, A9VHP7, B0RMW5, B1JXI9, B1KJM2, B1YHD4, B1YVH2, B2FKN7, B2SM13, B2SY86, B2U7J7, B3MQP7, B3NVC6, B4E9J1, B4H4U3, B4IDV8, B4JKK1, B4L629, B4M818, B4MSH7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GATA4	“down-regulates quantity by repression”	TDO2	“transcriptional regulation”
NR3C1	“down-regulates quantity by repression”	TDO2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	112
Likely benign	5
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

3283 predictions. Top by Δscore:

Variant	Effect	Δscore
12:71939088:AACAG:A	donor_loss	1.0000
12:71939089:ACA:A	donor_gain	1.0000
12:71939090:CA:C	donor_gain	1.0000
12:71939091:AG:A	donor_loss	1.0000
12:71939092:G:GG	donor_gain	1.0000
12:71941564:A:AG	acceptor_gain	1.0000
12:71941564:AT:A	acceptor_gain	1.0000
12:71941565:T:G	acceptor_gain	1.0000
12:71941565:T:TA	acceptor_gain	1.0000
12:71941570:C:A	acceptor_gain	1.0000
12:71941574:A:AG	acceptor_gain	1.0000
12:71941575:T:G	acceptor_gain	1.0000
12:71941579:T:A	acceptor_gain	1.0000
12:71944471:G:GT	donor_gain	1.0000
12:71949586:A:G	acceptor_gain	1.0000
12:71949653:ATA:A	donor_gain	1.0000
12:71949654:TA:T	donor_gain	1.0000
12:71949656:G:GG	donor_gain	1.0000
12:71972517:A:AG	acceptor_gain	1.0000
12:71972517:AGT:A	acceptor_gain	1.0000
12:71972518:G:GG	acceptor_gain	1.0000
12:71972518:GTG:G	acceptor_gain	1.0000
12:71979083:GAACC:G	donor_gain	1.0000
12:71979088:G:GG	donor_gain	1.0000
12:71994433:T:A	acceptor_gain	1.0000
12:71994434:GTCA:G	acceptor_loss	1.0000
12:71994435:TCA:T	acceptor_loss	1.0000
12:71994436:CA:C	acceptor_loss	1.0000
12:71994437:A:AC	acceptor_loss	1.0000
12:71994437:A:AG	acceptor_gain	1.0000

AlphaMissense

2681 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:155917468:T:A	W324R	0.999
4:155917468:T:C	W324R	0.999
4:155905151:C:G	H76D	0.998
4:155907733:T:A	W82R	0.998
4:155907733:T:C	W82R	0.998
4:155908933:G:C	R117P	0.998
4:155910050:T:C	F153L	0.998
4:155910052:C:A	F153L	0.998
4:155910052:C:G	F153L	0.998
4:155910056:A:C	S155R	0.998
4:155910058:T:A	S155R	0.998
4:155910058:T:G	S155R	0.998
4:155911500:T:A	W208R	0.998
4:155911500:T:C	W208R	0.998
4:155911504:T:C	L209P	0.998
4:155917472:G:C	R325T	0.998
4:155918224:T:C	L351P	0.998
4:155907731:T:C	L81P	0.997
4:155908924:G:C	R114P	0.997
4:155910069:G:C	R159P	0.997
4:155917473:A:C	R325S	0.997
4:155917473:A:T	R325S	0.997
4:155905139:T:C	F72L	0.996
4:155905141:T:A	F72L	0.996
4:155905141:T:G	F72L	0.996
4:155910078:A:T	E162V	0.996
4:155917439:T:C	L314P	0.996
4:155917472:G:T	R325I	0.996
4:155905140:T:C	F72S	0.995
4:155909001:T:C	F140L	0.995

dbSNP variants (sampled 300 via entrez): RS1000404763 (4:155915079 C>T), RS1000432122 (4:155905912 G>A), RS1000457047 (4:155914753 G>A), RS1000591507 (4:155910683 G>A), RS1000608860 (4:155910546 G>A), RS1000676934 (4:155912061 C>T), RS1000727775 (4:155916172 T>A,C,G), RS1000728527 (4:155904167 C>A), RS1000761492 (4:155904439 A>C,G,T), RS1000917951 (4:155910862 A>T), RS1001073102 (4:155916959 A>C,G), RS1001130222 (4:155916403 C>A,T), RS1001202743 (4:155916057 A>G,T), RS1001503146 (4:155903872 G>A), RS1001509327 (4:155906333 A>G,T)

Disease associations

OMIM: gene MIM:191070 | disease phenotypes: MIM:613003, MIM:608516, MIM:600627

GenCC curated gene-disease

Disease	Classification	Inheritance
familial hypertryptophanemia	Supportive	Autosomal recessive
attention deficit-hyperactivity disorder, susceptibility to, 7	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
familial hypertryptophanemia	Limited	AR

Mondo (3): attention deficit-hyperactivity disorder, susceptibility to, 7 (MONDO:0013076), major depressive disorder (MONDO:0002009), familial hypertryptophanemia (MONDO:0010907)

Orphanet (1): Hypertryptophanemia (Orphanet:2224)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000316	Hypertelorism
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000545	Myopia
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0001181	Adducted thumb
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001377	Limited elbow extension
HP:0001763	Pes planus
HP:0002342	Moderate intellectual disability
HP:0002761	Generalized joint hypermobility
HP:0003144	Increased serum serotonin
HP:0003361	Tryptophanuria
HP:0003623	Neonatal onset
HP:0007018	Attention deficit hyperactivity disorder
HP:0010982	Polygenic inheritance
HP:0025268	Stuttering
HP:0100490	Camptodactyly of finger
HP:0500134	Hypertryptophanemia
HP:5200321	Amplification of sexual behavior

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000492_2	Speech perception in dyslexia	5.000000e-08
GCST002932_9	Manganese levels	6.000000e-06
GCST009864_6	Fasting plasma glucose	9.000000e-07
GCST012490_344	Femur bone mineral density x serum urate levels interaction	3.000000e-17

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004336	speech perception
EFO:0004531	urate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003865	Depressive Disorder, Major	F03.600.300.375

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2140 (SINGLE PROTEIN), CHEMBL5169274 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 36,260 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL295124	BERBERINE	4	26,682
CHEMBL3545369	EPACADOSTAT	3	6,082
CHEMBL3989951	NAVOXIMOD	2	3,496

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10879346	Efficacy	3	antidepressants;mirtazapine;venlafaxine	Major Depressive Disorder
rs1386493	Dosage	3	methadone	Heroin Dependence
rs1487278	Efficacy	3	mirtazapine;venlafaxine	Depression
rs4570625	Efficacy	3	citalopram	Depressive Disorder

PharmGKB variants

16 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1386494	TPH2		0.00	0
rs1487278	TPH2	3	2.50	1	mirtazapine;venlafaxine
rs1843809	TPH2		0.00	0
rs4290270	TPH2		0.00	0
rs4570625	TPH2	3	0.00	1	citalopram
rs7305115	TPH2		0.00	0
rs10879346	TPH2	3	3.00	1	antidepressants;mirtazapine;venlafaxine
rs11178997	TPH2		0.00	0
rs11178998	TPH2		0.00	0
rs2129575	TPH2		0.00	0
rs2171363	TPH2		0.00	0
rs1386493	TPH2	3	2.25	1	methadone
rs10506645	TPH2		0.00	0
rs4760820	TPH2		0.00	0
rs9325202	TPH2		0.00	0
rs1487275	TPH2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 1.13.11.- Dioxygenases

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

Ligand	Action	Affinity	Parameter
navoximod	Inhibition	6.0	pIC50
LM10	Inhibition	5.25	pKi

Binding affinities (BindingDB)

62 measured of 79 human assays (79 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(3S)-1-[4-(6-fluoro-1H-indol-3-yl)phenyl]sulfonylpyrrolidin-3-ol	IC50	120 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
1-[4-(6-fluoro-1H-indol-3-yl)phenyl]sulfonyl-3-pyrimidin-5-ylpyrrolidin-3-ol	IC50	120 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
(3R)-1-[4-(6-fluoro-1H-indol-3-yl)phenyl]sulfonylpyrrolidin-3-ol	IC50	170 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
5-(6-fluoro-1H-indol-3-yl)-N- methylpyridin-2-amine	IC50	290 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
N-[5-[(1S)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl]-2-adamantyl]-1-phenylmethanesulfonamide	IC50	300 nM	US-10202388: Fused-ring compounds, pharmaceutical composition and uses thereof
6-fluoro-3-(6-methylpyridin-3- yl)-1H-indole	IC50	370 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
5-(6-fluoro-1H-indol-3-yl)- N,N-dimethylpyridin-2-amine	IC50	380 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
2-((5-(6-fluoro-1H-indol-3- yl)pyridin-2-yl)amino)ethanol	IC50	490 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
(3S,4R)-1-[4-(6-fluoro-1H-indol-3-yl)phenyl]sulfonylpyrrolidine-3,4-diol	IC50	530 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
4-(5-(6-fluoro-1H-indol-3- yl)pyridin-2-yl)morpholine	IC50	540 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
N1-(5-(6-fluoro-1H-indol-3- yl)pyridin-2-yl)-N2,N2- dimethylethane-1,2-diamine	IC50	540 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
4-(6-fluoro-1H-indol-3-yl)-N-[(2R)-2-hydroxypropyl]benzenesulfonamide	IC50	550 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
6-fluoro-3-(6-(piperidin-4- yloxy)pyridin-3-yl)-1H-indole	IC50	560 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
N-(3-((5-(6-fluoro-1H-indol-3- yl)pyridin-2-yl)amino)propyl) methanesulfonamide	IC50	620 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
2-amino-1-(4-(5-(6-fluoro-1H- indol-3-yl)pyridin-2- yl)piperazin-1-yl)ethanone	IC50	650 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
5-(6-fluoro-1H-indol-3-yl)-N- (1-(methylsulfonyl)piperidin- 4-yl)pyridin-2-amine	IC50	650 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
N-(2-((5-(6-fluoro-1H-indol-3- yl)pyridin-2-yl)amino)ethyl) methanesulfonamide	IC50	710 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
6-fluoro-3-(6-(4- methylpiperazin-1-yl)pyridin- 3-yl)-1H-indole	IC50	720 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
6-fluoro-3-(6-methoxypyridin- 3-yl)-1H-indole	IC50	730 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
2-((5-(6-fluoro-1H-indol-3- yl)pyridin-2- yl)amino)acetamide	IC50	790 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
3-[[4-(6-fluoro-1H-indol-3-yl)phenyl]sulfonylamino]cyclobutane-1-carboxamide	IC50	820 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
4-(6-fluoro-1H-indol-3-yl)-N-[(2S)-2-hydroxypropyl]benzenesulfonamide	IC50	840 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
4-(6-fluoro-1H-indol-3-yl)-N-[(2S)-1-hydroxypropan-2-yl]benzenesulfonamide	IC50	840 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
6-fluoro-3-(pyridin-3-yl)-1H- indole	IC50	850 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
6-fluoro-3-(2-methylpyridin-3- yl)-1H-indole	IC50	860 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
5-(6-fluoro-1H-indol-3-yl)-N- (piperidin-4-yl)pyridin-2- amine	IC50	870 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
N-(3-((5-(6-fluoro-1H-indol-3- yl)pyridin-2- yl)amino)propyl)acetamide	IC50	870 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
(3S,4S)-4-fluoro-1-[4-(6-fluoro-1H-indol-3-yl)phenyl]sulfonylpyrrolidin-3-amine	IC50	900 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
N-(1,1-dioxothiolan-3-yl)-4-(6-fluoro-1H-indol-3-yl)benzenesulfonamide	IC50	930 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
N-(1-(5-(6-fluoro-1H-indol-3- yl)pyridin-2-yl)piperidin-4- yl)methanesulfonamide	IC50	970 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
1-cyclohexyl-2-(4H-imidazo[1,5-a]indol-4-yl)ethanone	IC50	1000 nM	US-9981973: Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
N-(5-(6-fluoro-1H-indol-3- yl)pyridin-2-yl)acetamide	IC50	1000 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
4-(6-fluoro-1H-indol-3-yl)-N-[(2R)-1-hydroxypropan-2-yl]benzenesulfonamide	IC50	1000 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
5-(6-fluoro-1H-indol-3- yl)pyridin-2-amine	IC50	1100 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
[(2S)-4-[4-(6-fluoro-1H-indol-3-yl)phenyl]sulfonylpiperazin-2-yl]methanol	IC50	1100 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
6-fluoro-3-(6-((1- methylpiperidin-4- yl)oxy)pyridin-3-yl)-1H-indole	IC50	1200 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
5-(6-fluoro-1H-indol-3-yl)-N- (3-(methylsulfonyl)propyl) pyridin-2-amine	IC50	1200 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
5-(6-fluoro-1H-indol-3-yl)-N- (1-(methylsulfonyl)piperidin- 4-yl)pyridin-2-amine	IC50	1300 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
4-(6-fluoro-1H-indol-3-yl)-N-[(4-methyl-5-oxomorpholin-2-yl)methyl]benzenesulfonamide	IC50	1300 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
3-[[4-(6-fluoro-1H-indol-3-yl)phenyl]sulfonylamino]cyclobutane-1-carboxamide	IC50	1300 nM	US-10544095: 3-indol substituted derivatives, pharmaceutical compositions and methods for use
5-(6-fluoro-1H-indol-3-yl)-N- (2-(methylsulfonyl)ethyl) pyridin-2-amine	IC50	1500 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
5-(5,6-difluoro-1H-indol-3- yl)pyridin-2-amine	IC50	1600 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
2-((5-(6-fluoro-1H-indol-3- yl)pyridin-2-yl)amino)acetic acid	IC50	1600 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
2-amino-N-(1-(5-(6-fluoro- 1H-indol-3-yl)pyridin-2- yl)piperidin-4-yl)acetamide	IC50	1700 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
4-amino-N’-(3-chloro-5-fluorophenyl)-N-hydroxy-1,2,5-oxadiazole-3-carboximidamide	IC50	2510 nM	US-10155972: Screening method
5,6-difluoro-3-(pyridin-3-yl)- 1H-indole	IC50	2800 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
3-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-1H-indole	IC50	3980 nM	US-10155972: Screening method
6-fluoro-3-(5-methylpyridin-3- yl)-1H-indole	IC50	4500 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
N-(1-ethylpiperidin-4-yl)-5-(6- fluoro-1H-indol-3-yl)pyridin- 2-amine	IC50	4800 nM	US-9758505: 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
5-[(1R)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl]adamantan-2-ol	IC50	5500 nM	US-10202388: Fused-ring compounds, pharmaceutical composition and uses thereof

ChEMBL bioactivities

1044 potent at pChembl≥5 of 1244 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.47	IC50	3.42	nM	CHEMBL5220107
8.40	IC50	4	nM	CHEMBL4787695
8.02	IC50	9.6	nM	CHEMBL5203175
8.00	IC50	10	nM	CHEMBL4765090
7.94	IC50	11.6	nM	CHEMBL5991135
7.85	IC50	14	nM	CHEMBL4756155
7.82	IC50	15	nM	CHEMBL4780314
7.82	IC50	15	nM	CHEMBL4747779
7.80	IC50	15.8	nM	CHEMBL5767906
7.75	IC50	18	nM	CHEMBL4753714
7.75	IC50	18	nM	CHEMBL4791729
7.70	IC50	20	nM	CHEMBL4434743
7.70	IC50	20	nM	CHEMBL4466645
7.70	IC50	20	nM	CHEMBL4862796
7.70	IC50	20	nM	CHEMBL5945822
7.70	IC50	19.9	nM	CHEMBL5950224
7.68	IC50	21	nM	CHEMBL4798028
7.65	IC50	22.3	nM	CHEMBL5917176
7.60	IC50	25	nM	CHEMBL4747079
7.60	IC50	25	nM	CHEMBL4783665
7.60	IC50	25	nM	CHEMBL4785841
7.60	IC50	25	nM	CHEMBL4642346
7.58	IC50	26	nM	CHEMBL3947656
7.57	IC50	27	nM	CHEMBL3941937
7.55	IC50	28	nM	CHEMBL4173485
7.55	IC50	28	nM	CHEMBL4777219
7.54	IC50	29	nM	CHEMBL4165554
7.54	IC50	29	nM	CHEMBL5203175
7.54	IC50	29	nM	CHEMBL5218853
7.54	IC50	28.7	nM	CHEMBL5911062
7.53	IC50	29.3	nM	CHEMBL5879847
7.52	Ki	30	nM	CHEMBL355606
7.52	IC50	30	nM	CHEMBL3628599
7.52	IC50	30	nM	CHEMBL3628602
7.52	IC50	30	nM	CHEMBL4645973
7.52	IC50	30	nM	CHEMBL3629569
7.52	IC50	30	nM	BERBERINE
7.51	IC50	30.6	nM	CHEMBL4522927
7.50	EC50	32	nM	CHEMBL4577396
7.48	EC50	33	nM	CHEMBL4468203
7.47	IC50	34	nM	CHEMBL4753565
7.47	IC50	34	nM	CHEMBL4763934
7.46	EC50	35	nM	CHEMBL4544695
7.44	EC50	36	nM	CHEMBL4555603
7.44	IC50	36	nM	CHEMBL3628599
7.44	IC50	36	nM	CHEMBL4749726
7.42	IC50	37.9	nM	CHEMBL5775679
7.41	EC50	39	nM	CHEMBL4520696
7.40	IC50	40	nM	CHEMBL432537
7.40	IC50	40	nM	CHEMBL5219865

PubChem BioAssay actives

597 with measured affinity, of 1392 total; 50 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
2-[2-(3-bromothiophen-2-yl)-2-oxoethyl]-3-methylnaphthalene-1,4-dione	1916741: Inhibition of TDO in human BT-549 cells	ic50	0.0034	uM
1-(3-chloro-4-fluorophenyl)-6-fluorobenzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0040	uM
(S)-(7-chloroimidazo[1,5-a]pyridin-5-yl)-cyclohexylmethanol	1916193: Inhibition of human TDO	ic50	0.0096	uM
3-(3-chloro-4-fluorophenyl)-6-fluorobenzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0100	uM
3-(3-chloro-4-fluorophenyl)benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0140	uM
3-(4-chlorophenyl)benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0150	uM
3-(4-chloro-3-nitrophenyl)benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0150	uM
3-(3,4-dichlorophenyl)benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0180	uM
3-(4-chloro-3-fluorophenyl)benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0180	uM
2-imidazo[1,5-b]indazol-5-ylethanol	1548506: Inhibition of recombinant human TDO using L-tryptophan as substrate preincubated for 5 mins followed by substrate addition and measured after 15 mins by RapidFire-Mass spectrometry	ic50	0.0200	uM
5-(6-fluoro-1H-indol-3-yl)-2H-benzotriazole	1752072: Inhibition of human TDO2 expressed in mouse P815B cells assessed as kynurenine concentration formation using L-tryptophan as substrate incubated for 7 hrs by UPLC analysis	ic50	0.0200	uM
2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol	1548506: Inhibition of recombinant human TDO using L-tryptophan as substrate preincubated for 5 mins followed by substrate addition and measured after 15 mins by RapidFire-Mass spectrometry	ic50	0.0200	uM
3-pyridin-3-ylbenzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0210	uM
3-(6-chloro-3-pyridinyl)benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0250	uM
4-(3-chloro-4-fluoroanilino)-6-ethylimino-7-oxo-1H-indole-2-carboxylic acid	1687940: Inhibition of recombinant human TDO assessed as reduction in kynurenine formation using L-tryptophan as substrate incubated for 45 mins by microplate reader assay	ic50	0.0250	uM
3-[4-(2H-tetrazol-5-yl)phenyl]benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0250	uM
3-[3-chloro-4-(trifluoromethyl)phenyl]benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0250	uM
2-[5-(6-fluoro-1H-indol-3-yl)-3-methyl-1,1-dioxo-3H-1,2-benzothiazol-2-yl]acetamide	1331337: Inhibition of TDO2 in human A172 cells assessed as kynurenine formation after overnight incubation	ic50	0.0260	uM
(3R)-5-(6-fluoro-1H-indol-3-yl)-3-methyl-2,3-dihydro-1,2-benzothiazole 1,1-dioxide	1331337: Inhibition of TDO2 in human A172 cells assessed as kynurenine formation after overnight incubation	ic50	0.0270	uM
4-thiophen-3-yl-1,2-oxazol-5-amine	1354813: Inhibition of recombinant human TDO2 assessed as decrease in conversion of L-tryptophan to N-formylkynurenine preincubated for 5 mins followed by 0.2 mM substrate addition measured after 15 mins by RapidFire mass spectrometry based fluorescence assay	ic50	0.0280	uM
3-(3-nitrophenyl)benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0280	uM
(R)-(7-chloroimidazo[1,5-a]pyridin-6-yl)-cyclohexylmethanol	1916739: Inhibition of recombinant C-terminal His tagged TDO (unknown origin) expressed in Escherichia coli	ic50	0.0290	uM
4-thiophen-2-yl-1,2-oxazol-5-amine	1354813: Inhibition of recombinant human TDO2 assessed as decrease in conversion of L-tryptophan to N-formylkynurenine preincubated for 5 mins followed by 0.2 mM substrate addition measured after 15 mins by RapidFire mass spectrometry based fluorescence assay	ic50	0.0290	uM
6-fluoro-3-[(E)-2-pyridin-3-ylethenyl]-1H-indole	668565: Inhibition of liver TDO	ki	0.0300	uM
3-[[3-(4-methylpiperazine-1-carbonyl)phenyl]methyl]benzo[f]benzotriazole-4,9-dione	1252710: Inhibition of recombinant human TDO expressed in Escherichia coli incubated for 1 hr measured by fluorescence assay	ic50	0.0300	uM
3-[[4-(4-methylpiperazine-1-carbonyl)phenyl]methyl]benzo[f]benzotriazole-4,9-dione	1572836: Inhibition of TDO (unknown origin)	ic50	0.0300	uM
(E)-3-(8-fluoro-6,12-dioxoindolo[2,1-b]quinazolin-2-yl)prop-2-enoic acid	1659689: Inhibition of recombinant human TDO expressed in Escherichia coli BL21 using L-Trp as substrate incubated for 30 mins by enzymatic assay	ic50	0.0300	uM
16,17-dimethoxy-5,7-dioxa-13-azoniapentacyclo[11.8.0.02,10.04,8.015,20]henicosa-1(13),2,4(8),9,14,16,18,20-octaene	2130803: Inhibition of TDO (unknown origin)	ic50	0.0300	uM
1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol	1754170: Inhibition of recombinant human TDO2 expressed in Escherichia coli BL21 (DE3) assessed as reduction in N-formylkynurenine formation using L-tryptophan as substrate incubated for 30 mins by methylene blue reagent based assay	ic50	0.0300	uM
(1S,2S)-2-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]-1,2,3,4-tetrahydronaphthalen-1-ol	1548507: Inhibition of TDO in human SW48 cells after 24 hrs by NFK green reagent based assay	ec50	0.0320	uM
(5S)-5-cyclohexyl-5H-imidazo[5,1-a]isoindole	1548507: Inhibition of TDO in human SW48 cells after 24 hrs by NFK green reagent based assay	ec50	0.0330	uM
3-isoquinolin-7-ylbenzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0340	uM
3-(3,5-dichloro-4-fluorophenyl)benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0340	uM
(7S,8S)-8-hydroxy-7-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]-5,6,7,8-tetrahydronaphthalene-2-carboxamide	1548507: Inhibition of TDO in human SW48 cells after 24 hrs by NFK green reagent based assay	ec50	0.0350	uM
trans-(1R,2S)-2-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]cyclobutan-1-ol	1548507: Inhibition of TDO in human SW48 cells after 24 hrs by NFK green reagent based assay	ec50	0.0360	uM
3-(3-chlorophenyl)benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0360	uM
(1S,2S)-2-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]-7-methylsulfonyl-1,2,3,4-tetrahydronaphthalen-1-ol	1548507: Inhibition of TDO in human SW48 cells after 24 hrs by NFK green reagent based assay	ec50	0.0390	uM
cis-(1R,2S)-2-[[(6-bromo-1H-indazol-4-yl)amino]methyl]cyclohexan-1-ol	1916200: Inhibition of human TDO (19 to 388 aa) expressed in Escherichia coli Transetta (DE3) by nanodrop 2000c spectrophotometric analysis	ic50	0.0400	uM
8-nitroindolo[2,1-b]quinazoline-6,12-dione	1585056: Inhibition of TDO in human U87 MG cells using L-Trp as substrate after 8 hrs	ic50	0.0400	uM
3-(1H-indazol-5-yl)benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0420	uM
[5-(6-fluoro-1H-indol-3-yl)-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-3-yl]methanol	1331337: Inhibition of TDO2 in human A172 cells assessed as kynurenine formation after overnight incubation	ic50	0.0430	uM
(5S)-6-fluoro-5-[1-[4-(1-methylpyrazol-4-yl)phenyl]piperidin-4-yl]-5H-imidazo[5,1-a]isoindole	1562943: Inhibition of human TDO expressed in Escherichia coli Rosetta measured after 1 hr microplate reader analysis	ic50	0.0470	uM
3-[[3-(morpholine-4-carbonyl)phenyl]methyl]benzo[f]benzotriazole-4,9-dione	1252710: Inhibition of recombinant human TDO expressed in Escherichia coli incubated for 1 hr measured by fluorescence assay	ic50	0.0480	uM
(5S,6S)-6-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]-5,6,7,8-tetrahydroisoquinolin-5-ol	1548507: Inhibition of TDO in human SW48 cells after 24 hrs by NFK green reagent based assay	ec50	0.0480	uM
3-(4-nitrophenyl)benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0480	uM
4-(4,9-dioxobenzo[f]benzotriazol-3-yl)benzenesulfonamide	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0480	uM
3-(4-fluorophenyl)benzo[f]benzotriazole-4,9-dione	1704657: Inhibition of TDO (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins microplate spectrophotometry analysis	ic50	0.0490	uM
[4-(6-fluoro-1H-indol-3-yl)phenyl]urea	1916193: Inhibition of human TDO	ic50	0.0490	uM
trans-(1R,2S)-2-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]cyclohexan-1-ol	1548507: Inhibition of TDO in human SW48 cells after 24 hrs by NFK green reagent based assay	ec50	0.0500	uM
(7S,8S)-7-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]-5,6,7,8-tetrahydroisoquinolin-8-ol	1548507: Inhibition of TDO in human SW48 cells after 24 hrs by NFK green reagent based assay	ec50	0.0500	uM

CTD chemical–gene interactions

50 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
sodium arsenite	increases expression, decreases expression	2
Resveratrol	affects cotreatment, increases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
epacadostat	increases expression, decreases reaction	1
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
lead acetate	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
indeno(1,2,3-cd)pyrene	decreases reaction, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
cylindrospermopsin	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases reaction, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
1-methyltryptophan	decreases reaction, increases expression	1
incobotulinumtoxinA	increases expression	1
(+)-JQ1 compound	decreases expression	1
Cyclic AMP	decreases reaction, increases expression, affects cotreatment	1
Amiodarone	increases expression	1
Caffeine	decreases phosphorylation	1
Copper	affects cotreatment, increases expression	1
Demecolcine	increases expression	1
Dexamethasone	increases expression, decreases reaction	1
Succimer	affects cotreatment, increases expression	1

ChEMBL screening assays

152 unique, capped per target: 152 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1043001	Binding	Inhibition of tryptophan 2,3-dioxygenase	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

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8QJ	Abcam HCT 116 TDO2 KO	Cancer cell line	Male
CVCL_B9T0	Abcam A-549 TDO2 KO	Cancer cell line	Male
CVCL_D2HD	Abcam MCF-7 TDO2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00000375	PHASE4	COMPLETED	Continuation Electroconvulsive Therapy Vs Medication to Prevent Relapses in Patients With Major Depressive Disorder
NCT00049972	PHASE4	COMPLETED	Major Depressive Disorder Study In Adults
NCT00157547	PHASE4	COMPLETED	Quantitative EEG (QEEG) as a Predictor of Treatment Outcome in Depression
NCT00166114	PHASE4	COMPLETED	Depression, Epinephrine, and Platelet Function
NCT00177996	PHASE4	COMPLETED	Pharmacotherapy in Depression With Panic Spectrum
NCT00178074	PHASE4	COMPLETED	The Effects of Sleep Deprivation on Antidepressant Response
NCT00178100	PHASE4	COMPLETED	Paroxetine and Interpersonal Psychotherapy for Maintaining Health and Well-being in Elderly Individuals With Depression
NCT00182533	PHASE4	TERMINATED	Sertraline in Generalized Social Phobia With Co-Occurring Anxiety and Mood Disorders
NCT00186446	PHASE4	COMPLETED	Treatment of Nicotine Dependence and Acute Depression
NCT00188942	PHASE4	COMPLETED	A Neuroimaging Investigation of Brain Activity in Major Depressive Disorder and Bipolar Disorder
NCT00191932	PHASE4	COMPLETED	Switching to Duloxetine From Other Antidepressants
NCT00203723	PHASE4	TERMINATED	Use of Risperidone in ECT for Treatment Resistant Depression
NCT00208169	PHASE4	COMPLETED	Abilify Therapy for Reducing Comorbid Substance Abuse
NCT00208702	PHASE4	COMPLETED	Thyroid Medication and Antidepressants for Treating Major Depression
NCT00208715	PHASE4	COMPLETED	Provigil in Conjunction With SSRIs for the Treatment of Mild or Moderate Depression With Attendant Symptoms of Sleepiness and Fatigue.
NCT00209807	PHASE4	UNKNOWN	Effect of Escitalopram vs. Reboxetine on Gastro-intestinal Sensitivity of Patients With Major Depressive Disorder
NCT00222820	PHASE4	COMPLETED	Depression: The Search for Treatment-Relevant Phenotypes-Pilot Study
NCT00223197	PHASE4	COMPLETED	Pregnenolone Trial for Depression in Bipolar Disorders or Recurrent Major Depressive Disorder With Substance Abuse
NCT00226356	PHASE4	COMPLETED	Natural Supplements for Unipolar Depression
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00269334	PHASE4	UNKNOWN	Clinical Pharmacogenomics of Antidepressant Response
NCT00291239	PHASE4	UNKNOWN	Effect of Partial Sleep Deprivation on Cognition and Cytokines in Individuals With Major Depression
NCT00296686	PHASE4	TERMINATED	Sequential Tranylcypromine (TC), TC + Dextroamphetamine and TC + Triiodothyronine for Refractory Depression
NCT00296712	PHASE4	COMPLETED	Are Two Antidepressants a Good Initial Treatment for Depression?
NCT00296777	PHASE4	COMPLETED	Treatment of Depression Following Multiple Brain Tests
NCT00313417	PHASE4	TERMINATED	Creatine as a New Therapeutic Strategy in Depression
NCT00316160	PHASE4	COMPLETED	Sexual Functioning Study With Antidepressants
NCT00321152	PHASE4	COMPLETED	A Study of 6(S)-5-MTHF Among Serotonin Reuptake Inhibitor(SSRI)-Resistant Outpatients With Major Depressive Disorder (MDD)
NCT00330174	PHASE4	COMPLETED	Acamprosate in Alcoholics With Comorbid Anxiety or Depression
NCT00335205	PHASE4	UNKNOWN	A Placebo Controlled Trial of the Dopamine D-2 Receptor Agonist Ropinirole in Treatment of 60 Patients With Refractory Bipolar Depression.
NCT00353028	PHASE4	COMPLETED	Fluvoxamine Maleate in the Treatment of Depression/Depressive State : A Post-marketing Clinical Study in Children and Adolescents
NCT00357045	PHASE4	COMPLETED	Antidepressant Prophylaxis for Interferon-Induced Depression: Efficacy of Paroxetine
NCT00374426	PHASE4	COMPLETED	Preventing Depression Recurrence in Diabetes
NCT00384436	PHASE4	COMPLETED	Fixed Dose Comparison of Escitalopram to an Active Comparator in Severely Depressed Patients
NCT00404755	PHASE4	COMPLETED	Dichotic Listening as a Predictor of Medication Response in Depression
NCT00406848	PHASE4	COMPLETED	A Study Comparing the Efficacy and Safety of Duloxetine and Placebo for the Treatment of Depression in Elderly Patients
NCT00419003	PHASE4	COMPLETED	Research Study for Major Depressive Disorder: Investigation of Glutamate Medications
NCT00422162	PHASE4	COMPLETED	A Study Evaluating Duloxetine in Patients Hospitalized for Severe Depression
NCT00427128	PHASE4	COMPLETED	Prozac Treatment of Major Depression: Discontinuation Study
NCT00437125	PHASE4	COMPLETED	Study on the Tolerability of Duloxetine in Depressed Patients With Parkinson’s Disease