TPH1

Summary

TPH1 (tryptophan hydroxylase 1, HGNC:12008) is a protein-coding gene on chromosome 11p15.1, encoding Tryptophan 5-hydroxylase 1 (P17752). Oxidizes L-tryptophan to 5-hydroxy-l-tryptophan in the rate-determining step of serotonin biosynthesis.

This gene encodes a member of the aromatic amino acid hydroxylase family. The encoded protein catalyzes the first and rate limiting step in the biosynthesis of serotonin, an important hormone and neurotransmitter. Mutations in this gene have been associated with an elevated risk for a variety of diseases and disorders, including schizophrenia, somatic anxiety, anger-related traits, bipolar disorder, suicidal behavior, addictions, and others.

Source: NCBI Gene 7166 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 61 total
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004179

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12008
Approved symbol	TPH1
Name	tryptophan hydroxylase 1
Location	11p15.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000129167
Ensembl biotype	protein_coding
OMIM	191060
Entrez	7166

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000250018, ENST00000417164, ENST00000525406, ENST00000528338, ENST00000682019, ENST00000714230, ENST00000858102, ENST00000858103

RefSeq mRNA: 1 — MANE Select: NM_004179 NM_004179

CCDS: CCDS7829

Canonical transcript exons

ENST00000682019 — 11 exons

Exon	Start	End
ENSE00000886551	18033274	18033374
ENSE00000886552	18035959	18036142
ENSE00002168664	18029512	18029579
ENSE00003919349	18040646	18040788
ENSE00003921292	18046241	18046269
ENSE00004023246	18026490	18026625
ENSE00004023247	18029165	18029361
ENSE00004023248	18025575	18025701
ENSE00004023249	18022798	18022931
ENSE00004023251	18017555	18021165
ENSE00004023253	18023888	18023983

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 92.17.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 8.2213 / max 5979.5692, expressed in 54 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118907	8.0653	51
118906	0.0473	3
118909	0.0339	4
118910	0.0299	4
118905	0.0236	4
118908	0.0213	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	92.17	gold quality
blood vessel layer	UBERON:0004797	86.92	gold quality
rectum	UBERON:0001052	86.55	gold quality
ascending aorta	UBERON:0001496	84.62	gold quality
thoracic aorta	UBERON:0001515	84.57	gold quality
descending thoracic aorta	UBERON:0002345	84.13	gold quality
mucosa of sigmoid colon	UBERON:0004993	83.32	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.29	gold quality
pylorus	UBERON:0001166	77.73	gold quality
aorta	UBERON:0000947	77.55	gold quality
colonic mucosa	UBERON:0000317	76.38	gold quality
popliteal artery	UBERON:0002250	72.22	gold quality
tibial artery	UBERON:0007610	72.22	gold quality
jejunal mucosa	UBERON:0000399	71.26	gold quality
artery	UBERON:0001637	70.72	gold quality
small intestine Peyer’s patch	UBERON:0003454	69.24	gold quality
small intestine	UBERON:0002108	69.14	gold quality
duodenum	UBERON:0002114	68.53	gold quality
body of stomach	UBERON:0001161	67.13	gold quality
adenohypophysis	UBERON:0002196	67.04	gold quality
colonic epithelium	UBERON:0000397	66.93	gold quality
stomach	UBERON:0000945	66.75	gold quality
transverse colon	UBERON:0001157	66.12	gold quality
pituitary gland	UBERON:0000007	66.10	gold quality
pineal body	UBERON:0001905	65.90	silver quality
intestine	UBERON:0000160	65.85	gold quality
mucosa of stomach	UBERON:0001199	64.81	gold quality
large intestine	UBERON:0000059	64.60	gold quality
fundus of stomach	UBERON:0001160	64.59	gold quality
left uterine tube	UBERON:0001303	63.98	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-9154	yes	5859.89
E-CURD-114	yes	12.00
E-GEOD-81608	yes	8.11
E-GEOD-125970	yes	5.09
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ASCL1, ESR2, FEV, HES1, MITF, NFYB

miRNA regulators (miRDB)

24 targeting TPH1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-5693	99.24	66.67	1106
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-4684-5P	98.29	67.99	1650
HSA-MIR-561-5P	98.25	68.13	1365
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-5702	96.68	68.21	958
HSA-MIR-4435	95.90	65.47	1201

Literature-anchored findings (GeneRIF, showing 40)

• In a stable N-terminally truncated form of TPH that includes the catalytic domain, residue Phe-313 interacts with the substrate through ring stacking, thus predicting substrate specificity. (PMID:11747434)
• study did not support the involvement of 5-HTTLPR, TPH, MAO-A, or DRD4 polymorphisms in mood disorders (PMID:11992558)
• X-ray crystal structure analysis of a truncated functional form of TPH with the bound cofactor analogue 7,8-dihydro-L-biopterin provides the first atomic-resolution information for the catalytic domain and cofactor binding site of the enzyme. (PMID:12379098)
• THis enzyme’s immunoreactivity is altered by the genetic variation in postmortem brain samples of both suicide victims and controls. (PMID:12476329)
• Association of tryptophan hydroxylase gene polymorphisms and unipolar depression in a case-control study design. (PMID:12960746)
• Population-based association study tested the hypothesis that the tryptophan hydroxylase (TPH) A218C was associated with TPQ personality trait scores in a sample population of 209 young healthy Chinese. (PMID:14504413)
• Study assessed genetic factors influencing antidepressant response to fluoxetine. Results implicate TPH1 in general response to fluoxetine. (PMID:15052272)
• the denatured state properties of the AAAHs (TH, TPH and PAH) contribute significantly to the stability of these enzymes and their tolerance towards missense mutations (PMID:15135070)
• This study suggested that aggression in male subjects with Alzheimer’s disease may be genetically linked to polymorphic variation at the tryptophan hydroxylase gene. (PMID:15182943)
• There was a nearly doubling of the risk for childhood-onset schizophrenia associated with the AA genotype compared to other genotype groups in a Japanese sample (PMID:15211625)
• Five single nucleoside polymorphisms of the TPH1 gene were studied in postpartum women with depression or/and anxiety. Genotype frequency differences for the T27224C polymorphism were found between the comorbid and normal groups. (PMID:15544576)
• The positive heterosis effects with respect to nicotine addiction and personality support the idea that the TPH1 gene exerts pleiotropic effects. (PMID:15635702)
• Polymorphisms in the promoter region may influence the function of the TPH1 gene and further influence the proclivity of alcohol dependence in one ethnic group in Taiwan. (PMID:15654285)
• Tryptophan hydroxylasse polymorphisms not statistically diffrent in general anxiety disorder in Chinese. (PMID:15722951)
• Single nucleotide polymorphisms in the tryptophan hydroxylase gene are not associated with bipolar affective disorder. (PMID:15799788)
• te most common TPH-1 variants appear to carry no risk, while some of the less frequent variants might contribute to genetic predisposition to major depression (PMID:16165107)
• A218C polymorphism of the TPH gene does not play a major role in pathogenesis in major depressive disorder and does not serve as a modulator of antidepressant activity. (PMID:16314762)
• The TPH CC genotype in elderly victims of violent suicide points to the possible combined effect of the respective genetic factor and physiological changes during aging on the predisposition to this disorder. (PMID:16389591)
• Haplotype analyses showed that the rare 218A/-6526G haplotype was significantly not transmitted to probands with Attention deficit hyperactivity disorder. (PMID:16389593)
• Strong overall association between suicidal behavior and the A779C/A218C polymorphisms, supporting the involvement of TPH in the pathogenesis of suicidal behavior. (PMID:16450114)
• TPH1 may play a significant role in the aetiology of psychiatric disorders in the Han Chinese population. (PMID:16467214)
• The A218C SNP in TPH1 is not associated with completed suicide. (PMID:16538180)
• A218C polymorphism of the TPH gene may not be a susceptibility factor for suicidal behavior in this group of psychiatric patients but confirm that a family suicidal behavior history increases the proband’s suicide attempt risk. (PMID:16716203)
• Single marker association analyses showed two SNPs significantly associated with schizophrenia. A “sliding window” analysis attributed the strongest disease association to a haplotype configuration localized between the promoter region and intron 3. (PMID:16806098)
• polymorphisms play no significant roles in the pathogenesis and clinical symptomatologiy of panic dissorder in a Korean population. (PMID:16822601)
• The presence of the A/A haplotype of the TPH1 intron 7 polymorphism predicted a high level of adulthood harm avoidance in the presence of a hostile childhood environment. Findings also suggest a gene-environment correlation for novelty seeking in men. (PMID:16848783)
• It appears unlikely that the TPH1 and TPH2 genes play a significant role in the susceptibility to autism or to autism endophenotypes including severe obsessive-compulsive behaviors and self-stimulatory behaviors. (PMID:16958027)
• These findings do not support a major role for common 5-hydroxytryptamine transporter, TPH1, and monoamine oxidase A polymorphisms in contributing to susceptibility to premenstrual dysphoric disorder. (PMID:17026953)
• We studied the association between tryptophan hydroxylase 1 (TPH1) A218C polymorphism and treatment response in electroconvulsive therapy (ECT). (PMID:17066254)
• Since it is unlikely that TPH polymorphism alters serotonin biosynthesis, its association with migraine may be attributed to linkage disequilibrium with a functional variant within the TPH gene or a nearby gene. (PMID:17194593)
• study reports the learning process of decision-making in suicide attempters to be modulated by four serotonergic gene polymorphisms, 5HTTLPR, TPH1 A218C, MAOA u-VNTR, and TPH2 rs1118997 (PMID:17221847)
• Results describe regional differences in expression of TPH-1, SERT, 5-HT(3) and 5-HT(4) receptors in the stomach and duodenum. (PMID:17509016)
• TPH1 A779C C/A genotype was inversely associated with good treatment response to neuroleptics when compared with non-responding patients with schzophrenia (PMID:17521439)
• These findings found that tryptophan-hydroxylase-1 A218C polymorphism does not play a part in the genetic susceptibility to bulimia nervosa, but to be involved in predisposing bulimic patients to a more disturbed eating behavior and higher harm avoidance. (PMID:17548152)
• There were no significant associations between the polymorphisms or haplotypes of TPH1 and schizophrenia in our Japanese subjects. Our updated meta-analysis suggests the possible involvement of the TPH1 218A allele in schizophrenia. (PMID:17870198)
• TPH1 779A/C SNP is related to nicotine dependence and is associated with smoking status discriminating smokers from never-smokers and showed a tendency for an association with the degree of nicotine dependence. (PMID:17986837)
• TPH1 gene is implicated in depression. (PMID:18177948)
• Allele frequencies of three TPH2 variants and a TPH1 variant vary significantly among four ethnic groups with heroid adddiction. (PMID:18181017)
• It is suggested that TPH1 protein may be implicated in schizophrenia with beta-thalassemia simultaneously, present on the short arm of chromosome 11. (PMID:18221792)
• The result suggests that 218A/C variants of TPH1 cannot play a major role as predictor of treatment response as well as intolerance in Japanese patients with major depression. (PMID:18332644)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tph1a	ENSDARG00000029432
danio_rerio	tph1b	ENSDARG00000036082
mus_musculus	Tph1	ENSMUSG00000040046
drosophila_melanogaster	Trhn	FBGN0035187
caenorhabditis_elegans		WBGENE00006600

Paralogs (3): TPH2 (ENSG00000139287), PAH (ENSG00000171759), TH (ENSG00000180176)

Protein

Protein identifiers

Tryptophan 5-hydroxylase 1 — P17752 (reviewed: P17752)

Alternative names: Tryptophan 5-monooxygenase 1

All UniProt accessions (4): P17752, A0AAQ5BHT3, E7EMX4, E9PR49

UniProt curated annotations — full annotation on UniProt →

Function. Oxidizes L-tryptophan to 5-hydroxy-l-tryptophan in the rate-determining step of serotonin biosynthesis.

Subunit / interactions. Homotetramer. Interacts with DNAJC12.

Tissue specificity. Seems to be less widely expressed than isoform 1.

Post-translational modifications. Ubiquitinated, leading to its degradation by the proteasome. Ubiquitinated is triggered by phosphorylation. Phosphorylated; triggering degradation by the proteasome.

Pathway. Aromatic compound metabolism; serotonin biosynthesis; serotonin from L-tryptophan: step 1/2.

Similarity. Belongs to the biopterin-dependent aromatic amino acid hydroxylase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P17752-1	1	yes
P17752-2	2

RefSeq proteins (1): NP_004170* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001273	ArAA_hydroxylase	Family
IPR002912	ACT_dom	Domain
IPR005963	Trp_5_mOase	Family
IPR018301	ArAA_hydroxylase_Fe/CU_BS	Binding_site
IPR019773	Tyrosine_3-monooxygenase-like	Family
IPR019774	Aromatic-AA_hydroxylase_C	Domain
IPR036329	Aro-AA_hydroxylase_C_sf	Homologous_superfamily
IPR036951	ArAA_hydroxylase_sf	Homologous_superfamily
IPR041904	TrpOH_cat	Domain
IPR045865	ACT-like_dom_sf	Homologous_superfamily

Pfam: PF00351

Enzyme classification (BRENDA):

• EC 1.14.16.4 — tryptophan 5-monooxygenase (BRENDA: 37 organisms, 147 substrates, 229 inhibitors, 123 Km, 18 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	0.002–1.67	46
TETRAHYDROBIOPTERIN	0.0067–0.324	18
(6R)-L-ERYTHO-5,6,7,8-TETRAHYDROBIOPTERIN	0.0128–0.281	9
L-PHENYLALANINE	0.022–0.102	7
(6R)-L-ERYTHRO-5,6,7,8-TETRAHYDROBIOPTERIN	0.0179–0.796	4
2-AMINO-4-HYDROXY-6-METHYLTETRAHYDROPTERIDINE	0.055–0.125	4
2-AMINO-4-HYDROXY-6,7-DIMETHYL-5,6,7,8-TETRAHYDR	0.006–0.13	3
O2	0.039–0.273	3
TRYPTOPHAN	0.05–0.29	3
6-METHYL-TETRAHYDROPTERIN	0.053–0.802	2
6-METHYLTETRAHYDROPTERIN	0.0146–0.177	2
(6R)-5,6,7,8-TETRAHYDROBIOPTERIN	0.045	1
(7R)-5,6,7,8-TETRAHYDROBIOPTERIN	2.1	1
2-AMINO-4-HYDROXY-6-METHYL-5,6,7,8-TETRAHYDROPTE	0.05	1
2-AZAISOTRYPTOPHAN	0.0865	1

Catalyzed reactions (Rhea), 1 shown:

• (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + L-tryptophan + O2 = 5-hydroxy-L-tryptophan + (4aS,6R)-4a-hydroxy-L-erythro-5,6,7,8-tetrahydrobiopterin (RHEA:16709)

UniProt features (58 total): sequence conflict 17, helix 14, strand 9, binding site 8, turn 6, chain 1, domain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
8CJK	X-RAY DIFFRACTION	1.46
7ZIH	X-RAY DIFFRACTION	1.47
5TPG	X-RAY DIFFRACTION	1.5
7ZII	X-RAY DIFFRACTION	1.63
8CJI	X-RAY DIFFRACTION	1.65
8CJJ	X-RAY DIFFRACTION	1.66
8CJN	X-RAY DIFFRACTION	1.68
1MLW	X-RAY DIFFRACTION	1.71
3HF6	X-RAY DIFFRACTION	1.8
7ZIG	X-RAY DIFFRACTION	1.81
8CJL	X-RAY DIFFRACTION	1.83
3HF8	X-RAY DIFFRACTION	1.85
9WGZ	X-RAY DIFFRACTION	1.86
8CJO	X-RAY DIFFRACTION	1.87
7ZIF	X-RAY DIFFRACTION	1.87
5J6D	X-RAY DIFFRACTION	1.9
5L01	X-RAY DIFFRACTION	1.9
8CJM	X-RAY DIFFRACTION	1.9
3HFB	X-RAY DIFFRACTION	1.92
7ZIJ	X-RAY DIFFRACTION	1.95
9HE3	X-RAY DIFFRACTION	2.59

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17752-F1	87.96	0.65

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 (8): 235; 257; 265; 272; 277; 317; 336; 366

Post-translational modifications (1): 58

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-209931	Serotonin and melatonin biosynthesis
R-HSA-9031628	NGF-stimulated transcription

MSigDB gene sets: 115 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_EXOCYTOSIS, MORF_ZNF10, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, DIERICK_SEROTONIN_FUNCTION_GENES, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_SECRETION, GOBP_MAMMARY_GLAND_DEVELOPMENT, GOBP_INDOLE_CONTAINING_COMPOUND_METABOLIC_PROCESS

GO Biological Process (9): platelet degranulation (GO:0002576), obsolete serotonin biosynthetic process from L-tryptophan (GO:0006587), serotonin biosynthetic process (GO:0042427), positive regulation of fat cell differentiation (GO:0045600), bone remodeling (GO:0046849), mammary gland alveolus development (GO:0060749), regulation of hemostasis (GO:1900046), aromatic amino acid metabolic process (GO:0009072), phenol-containing compound biosynthetic process (GO:0046189)

GO Molecular Function (7): tryptophan 5-monooxygenase activity (GO:0004510), iron ion binding (GO:0005506), monooxygenase activity (GO:0004497), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced pteridine as one donor, and incorporation of one atom of oxygen (GO:0016714), metal ion binding (GO:0046872)

GO Cellular Component (3): cytosol (GO:0005829), neuron projection (GO:0043005), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amine-derived hormones	1
Nuclear Events (kinase and transcription factor activation)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
regulated exocytosis	1
establishment of localization in cell	1
serotonin metabolic process	1
indole-containing compound biosynthetic process	1
phenol-containing compound biosynthetic process	1
primary amino compound biosynthetic process	1
fat cell differentiation	1
positive regulation of cell differentiation	1
regulation of fat cell differentiation	1
tissue remodeling	1
anatomical structure development	1
mammary gland lobule development	1
hemostasis	1
regulation of biological process	1
regulation of body fluid levels	1
amino acid metabolic process	1
carboxylic acid metabolic process	1
biosynthetic process	1
phenol-containing compound metabolic process	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced pteridine as one donor, and incorporation of one atom of oxygen	1
transition metal ion binding	1
oxidoreductase activity	1
binding	1
catalytic activity	1
monooxygenase activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
cation binding	1
cytoplasm	1
plasma membrane bounded cell projection	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2088 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TPH1	SLC6A4	P31645	951
TPH1	HTR2A	P28223	901
TPH1	HTR1B	P28222	895
TPH1	HTR2B	P41595	892
TPH1	HTR2C	P28335	844
TPH1	YWHAZ	P29213	816
TPH1	HTR1D	P28221	801
TPH1	DRD4	P21917	798
TPH1	DDC	P20711	770
TPH1	MAOB	P27338	756
TPH1	ASMT	P46597	741
TPH1	MAOA	P21397	729
TPH1	HTR1A	P08908	687
TPH1	GCH1	P30793	680
TPH1	AANAT	Q16613	651

IntAct

25 interactions, top by confidence:

A	B	Type	Score
TPH1	DNAJC12	psi-mi:“MI:0915”(physical association)	0.620
PSTPIP1	TPH1	psi-mi:“MI:0915”(physical association)	0.560
TPH1	GORASP2	psi-mi:“MI:0915”(physical association)	0.560
TPH1	BECN1	psi-mi:“MI:0915”(physical association)	0.560
TPH1	ZMYM6	psi-mi:“MI:0915”(physical association)	0.560
BOD1	TPH1	psi-mi:“MI:0915”(physical association)	0.560
TPH1	YEATS4	psi-mi:“MI:0914”(association)	0.530
TPH1	CFL1	psi-mi:“MI:0915”(physical association)	0.400
TPH2	TPH1	psi-mi:“MI:0915”(physical association)	0.400
MYC		psi-mi:“MI:0914”(association)	0.350
CFTR	UBA6	psi-mi:“MI:2364”(proximity)	0.270
TPH1	PSTPIP1	psi-mi:“MI:0915”(physical association)	0.000
TPH1	GORASP2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (15): DNAJC12 (Affinity Capture-MS), MCM10 (Affinity Capture-MS), YEATS4 (Affinity Capture-MS), RFWD3 (Affinity Capture-MS), TPH1 (Two-hybrid), PSTPIP1 (Two-hybrid), CFL1 (Proximity Label-MS), YEATS4 (Affinity Capture-MS), DNAJC12 (Affinity Capture-MS), RFWD3 (Affinity Capture-MS), MCM10 (Affinity Capture-MS), YWHAZ (Reconstituted Complex), TPH1 (Affinity Capture-MS), TPH1 (Affinity Capture-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A0A060X6Z0, A8HQD7, A8X3V8, E5KBU3, E5KBU4, G8BAW7, O17446, O42091, O80452, P00365, P00439, P04176, P04177, P07101, P09810, P11982, P15274, P16331, P17276, P17289, P17290, P17532, P17752, P18459, P23225, P24529, P34466, P50998, P70080, P90925, P90986, Q0EAB8, Q0U2R3, Q10289, Q2HZ26, Q2KIH7, Q4W9F7, Q4WED9, Q54XS1, Q6BIV1

Diamond homologs: A0A060X6Z0, A8HQD7, A8X3V8, E5KBU3, E5KBU4, F5BFC8, O17446, O42091, P00439, P04176, P04177, P07101, P09810, P11982, P16331, P17276, P17289, P17290, P17532, P17752, P18459, P24529, P30967, P43334, P70080, P90925, P90986, Q0EAB8, Q2HZ26, Q2KIH7, Q54XS1, Q76IQ3, Q8CGU9, Q8CGV2, Q8IWU9, Q8XU39, Q92142, Q98D72, Q9A7V7, Q9KLB8

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
TPH1	“down-regulates quantity”	tryptophan	“chemical modification”
TPH1	“up-regulates quantity”	5-hydroxy-L-tryptophan	“chemical modification”
PRKACA	“up-regulates activity”	TPH1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	2
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1243 predictions. Top by Δscore:

Variant	Effect	Δscore
11:18021164:CT:C	acceptor_gain	1.0000
11:18022793:TGTA:T	donor_loss	1.0000
11:18022794:GTAC:G	donor_loss	1.0000
11:18022795:TA:T	donor_loss	1.0000
11:18022796:A:T	donor_loss	1.0000
11:18022927:GCATG:G	acceptor_gain	1.0000
11:18022928:CATG:C	acceptor_gain	1.0000
11:18022928:CATGC:C	acceptor_gain	1.0000
11:18022929:ATG:A	acceptor_gain	1.0000
11:18022930:TG:T	acceptor_gain	1.0000
11:18022930:TGC:T	acceptor_loss	1.0000
11:18022931:GCT:G	acceptor_loss	1.0000
11:18022932:C:CC	acceptor_gain	1.0000
11:18022932:CTA:C	acceptor_loss	1.0000
11:18023881:CTCTT:C	donor_loss	1.0000
11:18023882:TCTTA:T	donor_loss	1.0000
11:18023883:CTTAC:C	donor_loss	1.0000
11:18023884:TTAC:T	donor_loss	1.0000
11:18023885:TACT:T	donor_loss	1.0000
11:18023886:A:AC	donor_gain	1.0000
11:18023886:AC:A	donor_loss	1.0000
11:18023887:C:CT	donor_gain	1.0000
11:18023887:CT:C	donor_gain	1.0000
11:18023887:CTT:C	donor_gain	1.0000
11:18023935:G:C	donor_gain	1.0000
11:18023979:TAGCA:T	acceptor_gain	1.0000
11:18023980:AGCA:A	acceptor_gain	1.0000
11:18023981:GCA:G	acceptor_gain	1.0000
11:18023981:GCAC:G	acceptor_loss	1.0000
11:18023982:CA:C	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000195487 (11:18030829 T>A,C), RS1000253647 (11:18037638 GA>G,GAA), RS1000311751 (11:18021930 A>G), RS1000373197 (11:18029724 T>C), RS1000402244 (11:18044366 G>A,C), RS1000744191 (11:18032827 C>G,T), RS1000766162 (11:18021465 T>C), RS1001009014 (11:18042886 T>C), RS1001366831 (11:18023371 T>C), RS1001400585 (11:18045047 G>A,C), RS1001434096 (11:18038089 T>C), RS1001584675 (11:18031865 C>T), RS1001586945 (11:18038194 A>C), RS1001713346 (11:18023766 A>G), RS1001719339 (11:18024539 TA>T)

Disease associations

OMIM: gene MIM:191060 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006611_107	HDL cholesterol	2.000000e-08
GCST008963_1	Glucose homeostasis traits	7.000000e-07
GCST90002407_326	White blood cell count	7.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3831287 (PROTEIN FAMILY), CHEMBL5689 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 674 (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
CHEMBL2103855	TELOTRISTAT	4	310
CHEMBL2105695	TELOTRISTAT ETHYL	4	191
CHEMBL3348963	TELOTRISTAT ETIPRATE	4	120
CHEMBL4104957	RODATRISTAT	2	53

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1800532	Efficacy	3	lithium	Bipolar Disorder
rs1800532	Efficacy	4	antidepressants;citalopram;escitalopram;fluoxetine;paroxetine	Major Depressive Disorder

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1799913	TPH1		0.00	0
rs1800532	TPH1	3	0.00	2	lithium;antidepressants;citalopram;escitalopram;fluoxetine;paroxetine
rs623580	TPH1		0.00	0
rs211105	TPH1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Amino acid hydroxylases

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
rodatristat	Inhibition	7.48	pIC50
compound 23a [PMID: 33417443]	Inhibition	7.38	pIC50
telotristat ethyl	Inhibition	7.19	pIC50
TPT-004	Inhibition	7.11	pIC50
LP533401	Inhibition	6.23	pIC50

Binding affinities (BindingDB)

488 measured of 501 human assays (501 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	2 nM	US-9765092: Tricyclic piperidine compounds
5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide	IC50	2 nM	US-9765092: Tricyclic piperidine compounds
2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5-(4-methylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	2 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone	IC50	2 nM	US-9765092: Tricyclic piperidine compounds
5-(6-(2-(2-chloro-4-(methylsulfonamido)phenoxy)-acetyl)-5,6,7,8-tetrahydrothiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide	IC50	2 nM	US-9765092: Tricyclic piperidine compounds
1-(6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)pyrrolidin-2-one	IC50	2 nM	US-9765092: Tricyclic piperidine compounds
2-((6-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-chloropyridin-3-yl)oxy)-1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	2 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3-yl)oxy)ethanone	IC50	3 nM	US-9765092: Tricyclic piperidine compounds
2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	3 nM	US-9765092: Tricyclic piperidine compounds
2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	3 nM	US-9765092: Tricyclic piperidine compounds
6-chloro-5-(2-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide	IC50	3 nM	US-9765092: Tricyclic piperidine compounds
N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide	IC50	3 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-((2-methoxyethyl)(methyl)-amino)pyridin-3-yl)oxy)ethanone	IC50	3 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)-pyridin-3-yl)oxy)ethanone	IC50	3 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-((3S,5S)-3,5-dimethylpipe-ridin-1-yl)pyridin-3-yl)oxy)ethanone	IC50	3 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)oxy)ethanone	IC50	3 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl)oxy)ethanone	IC50	3 nM	US-9765092: Tricyclic piperidine compounds
2-(2-chloro-4-(morpholinomethyl)phenoxy)-1-(5-(2-fluoro-4-methoxyphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-morpholinophenoxy)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
2-((4-chloro-2-(dimethylamino)pyrimidin-5-yl)oxy)-1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-(trifluoromethyl)pyridin-3-yl)oxy)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
6-chloro-5-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
2-((2-chloro-5-fluoro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
2-((2-chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
(R)-6-chloro-5-(2-(5-(5-(dimethylcarbamoyl)-3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(3,4-dimethoxyphenyl)-7,8-dihydrothiazolo-[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(naphthalen-2-yloxy)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(2-fluoro-4-methoxyphenyl)-7,8-dihydrothiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(isoquinolin-7-yloxy)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
1-((5R)-5-(4-chloro-2-fluorophenyl)-4a,5-dihydro-thiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(7H)-yl)-2-(2-chloro-4-morpholinophenoxy)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo-[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)-7,8-dihydrothiazolo-[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-cyclopropylphenoxy)-ethanone	IC50	4 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)ethanone	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
1-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-(trifluoromethyl)phenoxy)ethanone	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
Methyl 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxylate	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
5-(6-(2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
6-chloro-5-(2-(5-(5-(dimethylcarbamoyl)-3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N-methylthiophene-2-carboxamide	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5-(thiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
2-((2-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3-yl)oxy)-1-(5-(2,3-difluoro-4-methylphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
2-((2-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3-yl)oxy)-1-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone	IC50	5 nM	US-9765092: Tricyclic piperidine compounds
(R)-1-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2’,3’:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone	IC50	5 nM	US-9765092: Tricyclic piperidine compounds

ChEMBL bioactivities

894 potent at pChembl≥5 of 917 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	IC50	2	nM	CHEMBL5818377
8.70	IC50	2	nM	CHEMBL5973645
8.70	IC50	2	nM	CHEMBL5912323
8.70	IC50	2	nM	CHEMBL6044111
8.70	IC50	2	nM	CHEMBL5918977
8.70	IC50	2	nM	CHEMBL5808085
8.70	IC50	2	nM	CHEMBL5966948
8.52	IC50	3	nM	CHEMBL5917746
8.52	IC50	3	nM	CHEMBL5893642
8.52	IC50	3	nM	CHEMBL5920265
8.52	IC50	3	nM	CHEMBL5907396
8.52	IC50	3	nM	CHEMBL5803526
8.52	IC50	3	nM	CHEMBL5762081
8.52	IC50	3	nM	CHEMBL5904262
8.52	IC50	3	nM	CHEMBL5883028
8.52	IC50	3	nM	CHEMBL5857512
8.52	IC50	3	nM	CHEMBL5764796
8.49	Kd	3.2	nM	CHEMBL5404510
8.40	IC50	4	nM	CHEMBL5800595
8.40	IC50	4	nM	CHEMBL5770521
8.40	IC50	4	nM	CHEMBL6015061
8.40	IC50	4	nM	CHEMBL5967798
8.40	IC50	4	nM	CHEMBL5956648
8.40	IC50	4	nM	CHEMBL5868648
8.40	IC50	4	nM	CHEMBL5769433
8.40	IC50	4	nM	CHEMBL5756165
8.40	IC50	4	nM	CHEMBL5921260
8.40	IC50	4	nM	CHEMBL5896848
8.40	IC50	4	nM	CHEMBL6048602
8.40	IC50	4	nM	CHEMBL5920962
8.40	IC50	4	nM	CHEMBL5941956
8.40	IC50	4	nM	CHEMBL6017170
8.40	IC50	4	nM	CHEMBL6054529
8.40	IC50	4	nM	CHEMBL5960227
8.40	IC50	4	nM	CHEMBL5883735
8.30	IC50	5	nM	CHEMBL6016397
8.30	IC50	5	nM	CHEMBL5828043
8.30	IC50	5	nM	CHEMBL5796038
8.30	IC50	5	nM	CHEMBL5923660
8.30	IC50	5	nM	CHEMBL5891493
8.30	IC50	5	nM	CHEMBL5766038
8.30	IC50	5	nM	CHEMBL6033870
8.30	IC50	5	nM	CHEMBL5937303
8.30	IC50	5	nM	CHEMBL6010581
8.30	IC50	5	nM	CHEMBL6015659
8.30	IC50	5	nM	CHEMBL5742788
8.30	IC50	5	nM	CHEMBL5934861
8.30	IC50	5	nM	CHEMBL5996694
8.30	IC50	5	nM	CHEMBL5913486
8.30	IC50	5	nM	CHEMBL5935973

PubChem BioAssay actives

304 with measured affinity, of 398 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
3-ethyl-8-[(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)methyl]-7-(oxetan-3-ylmethyl)purine-2,6-dione	2021107: Binding affinity to THP1 (unknown origin) assessed as equilibrium dissociation constant by surface plasmon resonance analysis	kd	0.0032	uM
(2S)-2-amino-3-[4-[[N’-[[2-piperidin-1-yl-6-[4-(trifluoromethyl)phenoxy]phenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0060	uM
(2S)-2-amino-3-[4-[[N’-[[2-(3-methoxyphenoxy)-6-piperidin-1-ylphenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0060	uM
(2S)-2-amino-3-[4-[[N’-[[2-(3-chlorophenoxy)-6-piperidin-1-ylphenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0060	uM
(2S)-2-amino-3-[4-[[N’-[[2-piperidin-1-yl-5-(1,3-thiazol-2-yl)phenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0070	uM
(2S)-2-amino-3-[4-[4-amino-6-[(2-phenylphenyl)methylamino]-1,3,5-triazin-2-yl]phenyl]propanoic acid	446767: Inhibition of human recombinant TPH1 by continuous fluorescence assay	ic50	0.0070	uM
(2S)-2-amino-3-[4-[[N’-[[2-(3-methylphenoxy)-6-piperidin-1-ylphenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0080	uM
(2S)-2-amino-3-[4-[[N’-[[2-piperidin-1-yl-6-[2-(trifluoromethyl)phenoxy]phenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0100	uM
(2S)-2-amino-3-[4-[[N’-[[2-(2-methoxyphenoxy)-6-piperidin-1-ylphenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0100	uM
(3S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-(3-sulfamoylphenyl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1434599: Inhibition of TPH1 (unknown origin)	ic50	0.0110	uM
(2S)-2-amino-3-[4-[[N’-[[2-piperidin-1-yl-6-(trifluoromethyl)phenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0110	uM
(2S)-2-amino-3-[4-[[N’-[[2-(4-chlorophenoxy)-6-piperidin-1-ylphenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0110	uM
(2S)-2-amino-3-[4-[[N’-[[2-(2-azabicyclo[2.2.1]heptan-2-yl)phenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0110	uM
(2S)-2-amino-3-[4-[[N’-[[2-(2-methylphenoxy)-6-piperidin-1-ylphenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0110	uM
(2S)-2-amino-3-[4-[[N’-[(2-methyl-6-piperidin-1-ylphenyl)methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0120	uM
(2S)-2-amino-3-[4-[[N’-[[2-(azepan-1-yl)-6-phenoxyphenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0130	uM
(2S)-2-amino-3-[4-[5-(naphthalen-2-ylmethylamino)pyrazin-2-yl]phenyl]propanoic acid	339459: Inhibition of TPH1	ic50	0.0130	uM
(3S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylsulfonylphenyl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1434599: Inhibition of TPH1 (unknown origin)	ic50	0.0140	uM
(2S)-2-amino-3-[4-[[N’-[[2-piperidin-1-yl-6-[3-(trifluoromethyl)phenoxy]phenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0140	uM
(2S)-2-amino-3-[4-[[N’-[(5-phenyl-2-piperidin-1-ylphenyl)methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0140	uM
(2S)-2-amino-3-[4-[4-amino-6-[[4-(4-methylphenyl)phenyl]methylamino]-1,3,5-triazin-2-yl]phenyl]propanoic acid	446767: Inhibition of human recombinant TPH1 by continuous fluorescence assay	ic50	0.0140	uM
(2S)-2-amino-3-[4-[[N’-[[2-(2-chlorophenoxy)-6-piperidin-1-ylphenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0150	uM
(2S)-2-amino-3-[4-[[N’-[[2-(4-methylphenoxy)-6-piperidin-1-ylphenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0150	uM
(2S)-2-amino-3-[4-[[N’-[[2-(2-methylpiperidin-1-yl)phenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0150	uM
(2S)-2-amino-3-[4-[[N’-[(5-chloro-2-piperidin-1-ylphenyl)methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0160	uM
(2S)-2-amino-3-[4-[[N’-[[2-(4-methoxyphenoxy)-6-piperidin-1-ylphenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0160	uM
(2S)-2-amino-3-[4-[[N’-[[2-(azepan-1-yl)phenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0160	uM
Telotristat	1278166: Inhibition of TPH1 (unknown origin)	ic50	0.0160	uM
(2S)-2-amino-3-[4-[[N’-[(2-methoxy-6-piperidin-1-ylphenyl)methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0180	uM
(3S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methoxyphenyl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1434599: Inhibition of TPH1 (unknown origin)	ic50	0.0190	uM
(2S)-2-amino-3-[4-[[N’-[[2-(azepan-1-yl)-6-methylphenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0190	uM
(2S)-3-[4-[4-[1-(1-adamantyl)ethylamino]-6-amino-1,3,5-triazin-2-yl]phenyl]-2-aminopropanoic acid	446767: Inhibition of human recombinant TPH1 by continuous fluorescence assay	ic50	0.0190	uM
(3S)-8-[2-amino-6-[(1R)-1-[4-(3,4-dimethylphenyl)-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1434599: Inhibition of TPH1 (unknown origin)	ic50	0.0200	uM
(2S)-2-amino-3-[4-[[N’-[[2-(3-methylpiperidin-1-yl)phenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0200	uM
(3S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-[3-(trifluoromethyl)phenyl]phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1434599: Inhibition of TPH1 (unknown origin)	ic50	0.0210	uM
(3S)-8-[2-amino-6-[(1R)-1-[4-(3,4-dichlorophenyl)-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1434599: Inhibition of TPH1 (unknown origin)	ic50	0.0220	uM
(3S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-(3,5-difluorophenyl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1434599: Inhibition of TPH1 (unknown origin)	ic50	0.0220	uM
(2S)-2-amino-3-[4-[[N’-[(2-piperidin-1-ylphenyl)methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0220	uM
(2S)-2-amino-3-[4-[[N’-[(5-methoxy-2-piperidin-1-ylphenyl)methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0220	uM
(3S)-8-[2-amino-6-[(1R)-2,2,2-trifluoro-1-[4-(4-methoxyphenyl)-2-(3-methylpyrazol-1-yl)phenyl]ethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1434599: Inhibition of TPH1 (unknown origin)	ic50	0.0230	uM
(3S)-8-[2-amino-6-[(1R)-1-[2-(3-tert-butylphenyl)-4-chlorophenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1434599: Inhibition of TPH1 (unknown origin)	ic50	0.0230	uM
(2S)-2-amino-3-[4-[4-amino-6-(naphthalen-2-ylmethylamino)-1,3,5-triazin-2-yl]phenyl]propanoic acid	339459: Inhibition of TPH1	ic50	0.0240	uM
(2S)-2-amino-3-[4-[2-amino-6-[2,2,2-trifluoro-1-[2-(furan-2-yl)phenyl]ethoxy]pyrimidin-4-yl]phenyl]propanoic acid	339459: Inhibition of TPH1	ic50	0.0240	uM
(2S)-2-amino-3-[4-[4-amino-6-[1-(4-phenylphenyl)ethylamino]-1,3,5-triazin-2-yl]phenyl]propanoic acid	446767: Inhibition of human recombinant TPH1 by continuous fluorescence assay	ic50	0.0240	uM
(3S)-8-[2-amino-6-[(1R)-2,2,2-trifluoro-1-(4-isoquinolin-6-ylphenyl)ethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1434599: Inhibition of TPH1 (unknown origin)	ic50	0.0250	uM
(2S)-2-amino-3-[4-[[N’-[[2-(3,5-dimethylpiperidin-1-yl)phenyl]methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0250	uM
(2S)-2-amino-3-[4-[[N’-[(5-methyl-2-piperidin-1-ylphenyl)methyl]carbamimidoyl]carbamoyl]phenyl]propanoic acid	1298868: Inhibition of TPH1 (unknown origin)	ic50	0.0250	uM
(3S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1278166: Inhibition of TPH1 (unknown origin)	ic50	0.0260	uM
(3S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylphenyl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1434599: Inhibition of TPH1 (unknown origin)	ic50	0.0260	uM
(3S)-8-[2-amino-6-[(1R)-2,2,2-trifluoro-1-[4-(2-methylsulfanylquinolin-6-yl)phenyl]ethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid	1434599: Inhibition of TPH1 (unknown origin)	ic50	0.0260	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sarpogrelate	decreases reaction, increases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Serotonin	affects abundance, increases abundance	2
sotorasib	affects cotreatment, increases expression	1
triptolide	decreases reaction, increases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	increases expression	1
Allura Red AC Dye	decreases reaction, increases expression	1
brilliant blue	increases expression	1
VX-agent	increases expression	1
sodium arsenite	decreases reaction, increases secretion, affects reaction	1
trametinib	increases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, increases expression	1
Carbon Tetrachloride	increases expression, decreases reaction	1
Cisplatin	decreases reaction, increases expression	1
Endosulfan	decreases expression	1
Glucose	affects reaction, increases secretion, decreases reaction	1
Hydrogen Peroxide	affects expression	1
N-Nitrosopyrrolidine	decreases expression	1
Silicon Dioxide	decreases expression	1
Tartrazine	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression	1
Butyric Acid	increases expression	1

ChEMBL screening assays

25 unique, capped per target: 24 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1016550	Binding	Inhibition of TPH1	Modulation of peripheral serotonin levels by novel tryptophan hydroxylase inhibitors for the potential treatment of functional gastrointestinal disorders. — J Med Chem
CHEMBL5374996	ADMET	Inhibition of recombinant MBP-tagged full length human THP1 using L-Trp as substrate assessed as formation of 5-HTP by measuring fluorescent property	Structure-Based Design of Xanthine-Imidazopyridines and -Imidazothiazoles as Highly Potent and In Vivo Efficacious Tryptophan Hydroxylase Inhibitors. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9UR	Ubigene HEK293 TPH1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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