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
• GTEx eGene: eQTL in 29 tissues, sQTL in 0 (q < 0.05)
• Drug target: yes — 1 curated mechanism-of-action drug, 3 via a complex or family; 4 molecules with ChEMBL bioactivity
• Approved drugs acting on a complex or family including it: 3 — Telotristat, Telotristat Ethyl, Telotristat Etiprate (Tryptophan 5-hydroxylase)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.92 (unconstrained)
• MANE Select transcript: NM_004179
• Notable: 61 clinical variants but no curated precision-oncology (CIViC) evidence yet

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

MANE Select: ENST00000682019

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 3: 1, TSL 5: 1

ENST00000682019, ENST00000250018, ENST00000417164, ENST00000525406, ENST00000528338, 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.

Highest expression (Bgee): buccal mucosa cell, blood vessel layer, rectum, ascending aorta, thoracic aorta.

Genetic regulation across tissues (GTEx eQTL / sQTL)

TPH1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 29 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 29 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Not Sun Exposed Suprapubic	eqtl	3.1e-14	-0.26	11:18084324:C:T
Skin Sun Exposed Lower leg	eqtl	3.6e-13	-0.22	11:18084324:C:T
Thyroid	eqtl	4.5e-13	-0.41	11:18113921:G:A
Cells Cultured fibroblasts	eqtl	3.2e-12	-0.30	11:18084324:C:T
Muscle Skeletal	eqtl	3.4e-10	-0.37	11:17949250:C:T
Nerve Tibial	eqtl	5.2e-10	-0.17	11:18084324:C:T
Adipose Subcutaneous	eqtl	4.7e-08	-0.37	11:17949250:C:T
Brain Cerebellum	eqtl	5.7e-07	-0.69	11:17949250:C:T
Adipose Visceral Omentum	eqtl	9.3e-07	-0.23	11:18084324:C:T
Esophagus Muscularis	eqtl	1.6e-06	-0.40	11:17949250:C:T
Brain Cerebellar Hemisphere	eqtl	3.2e-06	-0.31	11:18016571:C:A
Breast Mammary Tissue	eqtl	1.8e-05	-0.22	11:18084324:C:T
Esophagus Mucosa	eqtl	2.6e-05	-0.20	11:18076469:C:T
Spleen	eqtl	3.7e-05	-0.74	11:18056469:T:C
Artery Tibial	eqtl	4.0e-05	+0.39	11:18054711:T:A
Heart Atrial Appendage	eqtl	5.8e-05	-0.22	11:18084324:C:T
Lung	eqtl	1.3e-04	+0.19	11:18142024:TA:T
Pancreas	eqtl	1.4e-04	-0.28	11:18084324:C:T
Cells EBV-transformed lymphocytes	eqtl	1.6e-04	-0.65	11:18056469:T:C
Brain Anterior cingulate cortex BA24	eqtl	2.1e-04	-0.30	11:18076469:C:T

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

showing 100 of 289 tissues 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
colon	UBERON:0001155	63.85	gold quality
left coronary artery	UBERON:0001626	63.02	gold quality
oviduct epithelium	UBERON:0004804	62.91	silver quality
jejunum	UBERON:0002115	62.59	gold quality
mucosa of transverse colon	UBERON:0004991	62.02	gold quality
coronary artery	UBERON:0001621	61.67	gold quality
right coronary artery	UBERON:0001625	61.63	gold quality
tibial nerve	UBERON:0001323	61.25	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	60.75	gold quality
sigmoid colon	UBERON:0001159	60.51	gold quality
islet of Langerhans	UBERON:0000006	60.30	gold quality
calcaneal tendon	UBERON:0003701	59.87	gold quality
vermiform appendix	UBERON:0001154	59.76	gold quality
fallopian tube	UBERON:0003889	59.63	gold quality
ventricular zone	UBERON:0003053	59.47	gold quality
right ovary	UBERON:0002118	59.37	gold quality
skin of leg	UBERON:0001511	58.70	gold quality
skin of abdomen	UBERON:0001416	57.91	gold quality
prostate gland	UBERON:0002367	57.41	gold quality
pancreas	UBERON:0001264	57.09	gold quality
caecum	UBERON:0001153	56.85	gold quality
body of pancreas	UBERON:0001150	56.74	gold quality
body of uterus	UBERON:0009853	56.57	gold quality
left ovary	UBERON:0002119	56.48	gold quality
ganglionic eminence	UBERON:0004023	56.48	gold quality
ileal mucosa	UBERON:0000331	56.45	silver quality
ovary	UBERON:0000992	56.44	gold quality
gastrocnemius	UBERON:0001388	56.41	gold quality
zone of skin	UBERON:0000014	56.36	gold quality
muscle of leg	UBERON:0001383	56.31	gold quality
subcutaneous adipose tissue	UBERON:0002190	56.22	gold quality
granulocyte	CL:0000094	55.85	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	55.58	gold quality
cardia of stomach	UBERON:0001162	55.48	silver quality
muscle layer of sigmoid colon	UBERON:0035805	55.48	gold quality
right uterine tube	UBERON:0001302	55.46	gold quality
right lung	UBERON:0002167	55.43	gold quality
metanephros cortex	UBERON:0010533	55.41	gold quality
choroid plexus epithelium	UBERON:0003911	55.26	silver quality
sural nerve	UBERON:0015488	55.10	silver quality
endocervix	UBERON:0000458	55.00	gold quality
spleen	UBERON:0002106	54.94	gold quality
stromal cell of endometrium	CL:0002255	54.83	gold quality
ectocervix	UBERON:0012249	54.77	gold quality
cortical plate	UBERON:0005343	54.71	gold quality
muscle organ	UBERON:0001630	54.28	gold quality
bone marrow cell	CL:0002092	54.20	gold quality
paraflocculus	UBERON:0005351	54.06	silver quality
lymph node	UBERON:0000029	53.66	gold quality
minor salivary gland	UBERON:0001830	53.64	gold quality
uterine cervix	UBERON:0000002	53.31	gold quality
vagina	UBERON:0000996	53.30	gold quality
monocyte	CL:0000576	53.28	gold quality
mononuclear cell	CL:0000842	53.25	gold quality
leukocyte	CL:0000738	53.22	gold quality
hindlimb stylopod muscle	UBERON:0004252	53.07	silver quality
tendon	UBERON:0000043	52.94	gold quality
embryo	UBERON:0000922	52.84	gold quality
cortex of kidney	UBERON:0001225	52.83	gold quality
right atrium auricular region	UBERON:0006631	52.81	gold quality
anatomical system	UBERON:0000467	52.76	gold quality
cardiac atrium	UBERON:0002081	52.57	gold quality
multicellular organism	UBERON:0000468	52.54	gold quality
material anatomical entity	UBERON:0000465	52.52	gold quality
left lobe of thyroid gland	UBERON:0001120	52.49	gold quality
thyroid gland	UBERON:0002046	52.34	gold quality
female reproductive system	UBERON:0000474	52.25	gold quality
metanephros	UBERON:0000081	52.08	gold quality
mouth mucosa	UBERON:0003729	51.89	gold quality
saliva-secreting gland	UBERON:0001044	51.66	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

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Superior colliculi	tissue	22.0
Rectum	tissue	18.6	high
Stomach 1	tissue	14.5	high
Choroid plexus	tissue	11.5
Small intestine	tissue	10.9	high
Duodenum	tissue	9.8	high
Colon	tissue	8.7	high
Olfactory bulb	tissue	3.3
Cerebellum	tissue	2.8	medium
Periaqueductal gray	tissue	2.3
Cerebral cortex	tissue	2.2	low
Amygdala	tissue	2.2
Hippocampal formation	tissue	2.2
Entorhinal cortex	tissue	2.2
Retrosplenial and cingulate cortex	tissue	2.2
Temporal cortex	tissue	2.2
Insular cortex	tissue	2.2
Corpus callosum	tissue	2.1
Retrosplenial cortex	tissue	2.1
Basal ganglia	tissue	1.9	medium
Occipital cortex	tissue	1.9
Prefrontal cortex	tissue	1.8
Ventral forebrain	tissue	1.8
Retina	tissue	1.7
Septum	tissue	1.7
Somatosensory cortex	tissue	1.7
Pons	tissue	1.6
Motor cortex	tissue	1.6
Putamen	tissue	1.5
Hypothalamus	tissue	1.5
Substantia nigra	tissue	1.5
Hippocampus	tissue	1.5	medium
Skin 1	tissue	1.4	low
Nucleus accumbens	tissue	1.4
Midbrain	tissue	1.4
Medulla oblongata	tissue	1.4
Prostate	tissue	1.4	medium
Postcentral gyrus	tissue	1.4
Breast	tissue	1.3	medium
Thalamus	tissue	1.3
Locus coeruleus	tissue	1.3
Spinal cord	tissue	1.3
Pituitary gland	tissue	1.1
Bone marrow	tissue	1.1	medium
Appendix	tissue	1.1	medium
Testis	tissue	0.9	medium
Endometrium 1	tissue	0.8	low
Epididymis	tissue	0.8	low
Lung	tissue	0.7	low
Tonsil	tissue	0.7	medium
Lymph node	tissue	0.5	medium
Ovary	tissue	0.4	low
Skeletal muscle	tissue	0.4	medium
Spleen	tissue	0.4	medium
Adipose tissue	tissue	0.3	not detected
Urinary bladder	tissue	0.3	medium
Frontal cortex	tissue	0.3
Thyroid gland	tissue	0.3	medium
Kidney	tissue	0.3	medium
Thymus	tissue	0.3

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Median raphe nucleus (22.5), Supraoptic nucleus (8.0), Dorsal raphe nucleus (3.8), Pontine raphe nucleus (3.7), Blood vessel (2.7).

Regulation

Is transcription factor: no

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

miRNA regulators (miRDB)

Targeting TPH1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

24 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 1.69e-08, LOEUF 0.921, missense Z 1.08 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000682019 — one region, missense o/e 0.93.

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

4 orthologs

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

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

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:98796) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 19 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased serotonin level	2
enlarged heart	1
respiratory distress	1
increased heart rate	1
fatigue	1
decreased cardiac output	1
pallor	1
increased osteoblast cell number	1
decreased cardiac muscle contractility	1
impaired glucose tolerance	1
abnormal serotonin level	1
increased bone mass	1
decreased physiological sensitivity to xenobiotic	1
decreased pancreatic beta cell mass	1
abnormal heart left ventricle pressure	1
decreased pancreatic beta cell proliferation	1
decreased cardiac stroke volume	1
increased bone ossification	1
increased osteoblast proliferation	1

Additional cross-species homologs

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

Organism	UniProt	Identity	Method
Macaca mulatta	Q2HZ26	98.8%	Diamond
Rattus norvegicus	P04176	98.2%	Diamond
Oryctolagus cuniculus	P17290	95.5%	Diamond
Equus caballus	Q0EAB8	95.1%	Diamond
Bos taurus	Q2KIH7	92.5%	Diamond
Oncorhynchus mykiss	A0A060X6Z0	89.8%	Diamond
Anguilla anguilla	O42091	89.8%	Diamond
Canis lupus familiaris	Q76IQ3	88.3%	Diamond
Caenorhabditis briggsae	A8X3V8	88.1%	Diamond
Gallus gallus	P70080	88.1%	Diamond
Caenorhabditis elegans	P90986	88.1%	Diamond
Xenopus laevis	Q92142	88.1%	Diamond
Phasianidae sp.	P11982	78.9%	Diamond
Chromobacterium violaceum ATCC 12472	P30967	73.9%	Diamond
Ralstonia pseudosolanacearum GMI1000	Q8XU39	73.9%	Diamond
Pinus taeda	E5KBU3	69.8%	Diamond
Physcomitrium patens	E5KBU4	69.8%	Diamond
Caulobacter vibrioides CB15	Q9A7V7	63.4%	Diamond
Pseudomonas aeruginosa PAO1	P43334	59.3%	Diamond
Vibrio cholerae O1 biovar El Tor str. N16961	Q9KLB8	59.3%	Diamond
Chlamydomonas reinhardtii	A8HQD7	59.0%	Diamond
Schistosoma mansoni	O17446	56.1%	Diamond
Dictyostelium discoideum	Q54XS1	55.5%	Diamond
Aquifex aeolicus VF5	O67085	50.0%	Diamond
Mesorhizobium japonicum MAFF 303099	Q98D72	49.8%	Diamond
Methanocaldococcus jannaschii DSM 2661	Q58054	47.8%	Diamond
Streptomyces coeruleorubidus	F5BFC8	39.0%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
SAAL1	protein-coding	113174
MRGPRX3	protein-coding	117195
SERGEF	protein-coding	26297
KCNC1	protein-coding	3746
MYOD1	protein-coding	4654
LINC02729	ncRNA	102723330

Protein

Protein identifiers

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

Alternative names: Tryptophan 5-monooxygenase 1

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

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)

• (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 (64 total): helix 21, sequence conflict 17, strand 9, binding site 8, turn 5, chain 1, domain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

21 structures by resolution:

PDB	Title	Method	Resolution (Å)
8CJK	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-06-098	X-RAY DIFFRACTION	1.46
7ZIH	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor AG-01-128	X-RAY DIFFRACTION	1.47
5TPG	Optimization of spirocyclic proline tryptophanhydroxylase-1 inhibitors	X-RAY DIFFRACTION	1.5
7ZII	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-05-193	X-RAY DIFFRACTION	1.63
8CJI	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-07-052	X-RAY DIFFRACTION	1.65
8CJJ	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-06-057	X-RAY DIFFRACTION	1.66
8CJN	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-06-070	X-RAY DIFFRACTION	1.68
1MLW	Crystal structure of human tryptophan hydroxylase with bound 7,8-dihydro-L-biopterin …	X-RAY DIFFRACTION	1.71
3HF6	Crystal structure of human tryptophan hydroxylase type 1 with bound LP-521834 and FE	X-RAY DIFFRACTION	1.8
7ZIG	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-05-060	X-RAY DIFFRACTION	1.81
8CJL	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor TPT-004	X-RAY DIFFRACTION	1.83
3HF8	Crystal structure of human tryoptophan hydroxylase type 1 with bound LP-533401 and Fe	X-RAY DIFFRACTION	1.85
9WGZ	Tryptophan hydroxylase mutant - Y235S	X-RAY DIFFRACTION	1.86
8CJO	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-06-004	X-RAY DIFFRACTION	1.87
7ZIF	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-480	X-RAY DIFFRACTION	1.87
5J6D	Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors	X-RAY DIFFRACTION	1.9
5L01	Tryptophan 5-hydroxylase in complex with inhibitor …	X-RAY DIFFRACTION	1.9
8CJM	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-07-047	X-RAY DIFFRACTION	1.9
3HFB	Crystal structure of human tryoptophan hydroxylase type 1 with LP-534193	X-RAY DIFFRACTION	1.92
7ZIJ	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-05-080	X-RAY DIFFRACTION	1.95
9HE3	Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor LP778902	X-RAY DIFFRACTION	2.59

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Oxidoreductases, Metabolic proteins, Predicted intracellular proteins, FDA approved drug targets, Small molecule drugs

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH uncertain · IF approved

Functional residue map

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

Ligand- & substrate-binding residues (8)

Position	Role
235	L-tryptophan
257	L-tryptophan
265	L-tryptophan
272	Fe cation
277	Fe cation
317	Fe cation
336	L-tryptophan
366	L-tryptophan

Post-translational modifications (1)

Type	Positions
Phosphoserine	58

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 10; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

10 pathways:

ID	Pathway	Evidence
R-HSA-9031628	NGF-stimulated transcription	curated
R-HSA-209931	Serotonin and melatonin biosynthesis	curated
R-HSA-1430728	Metabolism	—
R-HSA-209776	Metabolism of amine-derived hormones	—
R-HSA-71291	Metabolism of amino acids and derivatives	—
R-HSA-198725	Nuclear Events (kinase and transcription factor activation)	—
R-HSA-162582	Signal Transduction	—
R-HSA-187037	Signaling by NTRK1 (TRKA)	—
R-HSA-166520	Signaling by NTRKs	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—

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 (5): platelet degranulation (GO:0002576), serotonin biosynthetic process (GO:0042427), 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

8 top-level categories:

Category	Pathways
Metabolism of amine-derived hormones	1
Nuclear Events (kinase and transcription factor activation)	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by NTRKs	1
Signaling by NTRK1 (TRKA)	1
Metabolism of amino acids and derivatives	1
Metabolism	1
Signal Transduction	1

GO top-level categories

25 GO namespaces:

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
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

showing 15 of 1,686 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TPH1	SLC6A4	P31645	927
TPH1	HTR2A	P28223	900
TPH1	HTR1B	P28222	881
TPH1	HTR2B	P41595	875
TPH1	HTR2C	P28335	838
TPH1	HTR1D	P28221	789
TPH1	DRD4	P21917	784
TPH1	DDC	P20711	766
TPH1	ASMT	P46597	744
TPH1	MAOB	P27338	743
TPH1	AANAT	Q16613	738
TPH1	MAOA	P21397	726
TPH1	YWHAZ	P29213	706
TPH1	CHGA	P10645	667
TPH1	HTR1A	P08908	655

IntAct

Human interaction partners of TPH1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

9 partners by confidence:

Partner	Interaction type	MIscore	Records
DNAJC12	physical association	0.620	1
GORASP2	physical association	0.560	5
BECN1	physical association	0.560	3
BOD1	physical association	0.560	3
PSTPIP1	physical association	0.560	3
ZMYM6	physical association	0.560	3
YEATS4	association	0.530	2
CFL1	physical association	0.400	1
TPH2	physical association	0.400	1

BioGRID (14 interactions; top human partners by supporting records): DNAJC12 (Affinity Capture-MS; 2 records), MCM10 (Affinity Capture-MS; 2 records), RFWD3 (Affinity Capture-MS; 2 records), YEATS4 (Affinity Capture-MS; 2 records), APP (Reconstituted Complex), GORASP2 (Two-hybrid), PSTPIP1 (Two-hybrid), RELA (Affinity Capture-MS), TPH2 (Affinity Capture-MS), YWHAZ (Reconstituted Complex)

SIGNOR signaling

3 signaling 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

Ligand–receptor pairs (CellPhoneDB) (13)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

13 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
HTR3A;HTR3B;HTR3C;HTR3D;HTR3E		Signaling by Serotonin
HTR1E		Signaling by Serotonin
HTR4		Signaling by Serotonin
HTR1F		Signaling by Serotonin
HTR2A		Signaling by Serotonin
HTR6		Signaling by Serotonin
HTR1A		Signaling by Serotonin
HTR1B		Signaling by Serotonin
HTR5A		Signaling by Serotonin
HTR7		Signaling by Serotonin
HTR2B		Signaling by Serotonin
HTR1D		Signaling by Serotonin
HTR2C		Signaling by Serotonin

Disease & clinical

Genetic variants

Variant evidence for TPH1: 61 ClinVar records (0 pathogenic / likely pathogenic); 2 PharmGKB clinical annotations; 3 GWAS associations.

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

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 1,029):

Position(s)	Effect	Δscore	Sites
11:18022796–18022797	donor_loss	1.0000	3
11:18022932–18022933	acceptor_loss	1.0000	6
11:18023886–18023887	donor_loss	1.0000	4
11:18023935	donor_gain	1.0000
11:18023984–18023985	acceptor_loss	1.0000	5
11:18029362–18029363	acceptor_loss	1.0000	6
11:18029370	acceptor_gain	1.0000
11:18029511	donor_loss	1.0000	2
11:18029580–18029581	acceptor_loss	1.0000	5
11:18030660	donor_gain	1.0000

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Uterine Corpus Endometrial Carcinoma)

Disease associations

OMIM: gene MIM:191060 | disease phenotypes:

GWAS associations

3 associations:

Study	Trait	p-value
GCST90002407_394	White blood cell count	7e-9
GCST006611_99	HDL cholesterol	2e-8
GCST008963_1	Glucose homeostasis traits	7e-7

EFO canonical traits (from GWAS)

1 canonical traits:

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)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the TPH1 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
RODATRISTAT ETHYL	Small molecule	2

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes TPH1 — the drug acts on the assembly or class, not necessarily on this subunit alone.

3 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
TELOTRISTAT	Tryptophan 5-hydroxylase	2	4
TELOTRISTAT ETHYL	Tryptophan 5-hydroxylase	2	4
TELOTRISTAT ETIPRATE	Tryptophan 5-hydroxylase	2	4

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 716 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

4 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL2103855	TELOTRISTAT	4	335
CHEMBL2105695	TELOTRISTAT ETHYL	4	202
CHEMBL3348963	TELOTRISTAT ETIPRATE	4	125
CHEMBL4104957	RODATRISTAT	2	54

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

2 annotations by evidence level (1 strongest → 4):

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

PharmGKB variants

1 variants:

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

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

2 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1800532	escitalopram	Efficacy	Genotypes GT + TT are associated with decreased response to escitalopram in people with Depression as compared to genotype GG.	PMID:31721892
rs1800532	citalopram	Efficacy	Genotypes GT + TT are associated with decreased response to citalopram in people with Depressive Disorder, Major as compared to genotype GG.	PMID:23221997

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)

768 measured of 785 human assays (785 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-[(12R)-12-(4-chloro-2-fluorophenyl)-5-thia-2,7,11-triazatricyclo[6.4.0.02,6]dodeca-3,6,8-trien-11-yl]-2-(2-chloro-4-morpholin-4-ylphenoxy)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	increases expression, decreases reaction	1
brilliant blue	increases expression	1
VX-agent	increases expression	1
sodium arsenite	affects reaction, decreases reaction, increases secretion	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Carbon Tetrachloride	increases expression, decreases reaction	1
Cisplatin	increases expression, decreases reaction	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)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for TPH1 across ~30M SureChEMBL compounds — explore on Sugi Predict.