TCF4

Summary

TCF4 (transcription factor 4, HGNC:11634) is a protein-coding gene on chromosome 18q21.2, encoding Transcription factor 4 (P15884). Transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5-motif. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box (‘E-box’) binding site (‘CANNTG’) - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described.

Source: NCBI Gene 6925 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Pitt-Hopkins syndrome (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 128
• Clinical variants (ClinVar): 1,196 total — 173 pathogenic, 92 likely-pathogenic
• Phenotypes (HPO): 3
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 2 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 65 downstream targets (CollecTRI)
• MANE Select transcript: NM_001083962

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11634
Approved symbol	TCF4
Name	transcription factor 4
Location	18q21.2
Locus type	gene with protein product
Status	Approved
Aliases	SEF2-1B, ITF2, bHLHb19, E2-2
Ensembl gene	ENSG00000196628
Ensembl biotype	protein_coding
OMIM	602272
Entrez	6925

Gene structure

Transcript identifiers

Ensembl transcripts: 109 — 80 protein_coding, 15 protein_coding_CDS_not_defined, 9 nonsense_mediated_decay, 5 retained_intron

ENST00000354452, ENST00000356073, ENST00000398339, ENST00000457482, ENST00000537578, ENST00000537856, ENST00000540999, ENST00000543082, ENST00000544241, ENST00000561831, ENST00000561992, ENST00000562030, ENST00000562543, ENST00000562607, ENST00000562638, ENST00000562680, ENST00000562847, ENST00000563686, ENST00000563760, ENST00000563824, ENST00000563888, ENST00000564228, ENST00000564343, ENST00000564403, ENST00000564999, ENST00000565018, ENST00000565124, ENST00000565393, ENST00000565580, ENST00000565908, ENST00000566279, ENST00000566286, ENST00000566376, ENST00000566514, ENST00000566777, ENST00000567880, ENST00000568147, ENST00000568169, ENST00000568186, ENST00000568673, ENST00000568740, ENST00000569012, ENST00000569357, ENST00000570146, ENST00000570177, ENST00000570287, ENST00000590810, ENST00000616053, ENST00000625716, ENST00000625925, ENST00000626425, ENST00000626466, ENST00000626584, ENST00000626595, ENST00000626631, ENST00000627136, ENST00000627320, ENST00000627568, ENST00000627685, ENST00000627784, ENST00000628078, ENST00000628360, ENST00000628391, ENST00000628636, ENST00000628689, ENST00000629343, ENST00000629387, ENST00000630224, ENST00000630268, ENST00000630319, ENST00000630712, ENST00000630720, ENST00000630828, ENST00000631043, ENST00000635822, ENST00000635990, ENST00000636400, ENST00000636710, ENST00000636751, ENST00000636822, ENST00000637068, ENST00000637115, ENST00000637169, ENST00000637239, ENST00000637250, ENST00000637500, ENST00000637923, ENST00000637941, ENST00000638154, ENST00000643689, ENST00000674598, ENST00000674764, ENST00000675707, ENST00000856114, ENST00000856115, ENST00000856116, ENST00000856117, ENST00000856118, ENST00000856119, ENST00000856120, ENST00000856121, ENST00000936493, ENST00000936494, ENST00000936495, ENST00000936496, ENST00000936497, ENST00000936498, ENST00000941604, ENST00000941605

RefSeq mRNA: 46 — MANE Select: NM_001083962 NM_001083962, NM_001243226, NM_001243227, NM_001243228, NM_001243230, NM_001243231, NM_001243232, NM_001243233, NM_001243234, NM_001243235, NM_001243236, NM_001306207, NM_001306208, NM_001330604, NM_001330605, NM_001348211, NM_001348212, NM_001348213, NM_001348214, NM_001348215, NM_001348216, NM_001348217, NM_001348218, NM_001348219, NM_001348220, NM_001369567, NM_001369568, NM_001369569, NM_001369570, NM_001369571, NM_001369572, NM_001369573, NM_001369574, NM_001369575, NM_001369576, NM_001369577, NM_001369578, NM_001369579, NM_001369580, NM_001369581, NM_001369582, NM_001369583, NM_001369584, NM_001369585, NM_001369586, NM_003199

CCDS: CCDS11960, CCDS42438, CCDS58623, CCDS58624, CCDS58625, CCDS58626, CCDS58627, CCDS58628, CCDS58629, CCDS58630, CCDS58631, CCDS59321, CCDS77191, CCDS77192, CCDS82255, CCDS86671, CCDS86672

Canonical transcript exons

ENST00000354452 — 20 exons

Exon	Start	End
ENSE00001103792	55228847	55229076
ENSE00001428057	55232509	55232671
ENSE00003464211	55234548	55234683
ENSE00003505563	55350874	55351003
ENSE00003519932	55254497	55254700
ENSE00003540131	55587045	55587136
ENSE00003553770	55403454	55403518
ENSE00003564895	55269831	55269963
ENSE00003566400	55261466	55261533
ENSE00003595877	55257315	55257391
ENSE00003597346	55228221	55228361
ENSE00003605243	55259949	55260027
ENSE00003613288	55461019	55461115
ENSE00003613679	55279551	55279656
ENSE00003657177	55275619	55275752
ENSE00003675281	55464076	55464137
ENSE00003688806	55585280	55585352
ENSE00003766717	55222185	55228030
ENSE00003772200	55588038	55588192
ENSE00003784054	55350359	55350408

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.4025 / max 932.9849, expressed in 1517 samples.

FANTOM5 promoters (49 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172075	10.4417	1496
172079	5.3279	1229
172023	4.0478	862
172036	3.7542	663
172045	1.3120	121
172024	1.2227	531
172022	0.8394	381
172048	0.6283	214
172021	0.6148	271
172076	0.5650	241

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.67	gold quality
skin of hip	UBERON:0001554	99.39	gold quality
pericardium	UBERON:0002407	99.30	gold quality
entorhinal cortex	UBERON:0002728	99.29	gold quality
parietal lobe	UBERON:0001872	99.20	gold quality
calcaneal tendon	UBERON:0003701	99.18	gold quality
postcentral gyrus	UBERON:0002581	99.17	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.12	gold quality
synovial joint	UBERON:0002217	99.11	gold quality
ganglionic eminence	UBERON:0004023	99.09	gold quality
nipple	UBERON:0002030	99.08	gold quality
CA1 field of hippocampus	UBERON:0003881	99.06	gold quality
cranial nerve II	UBERON:0000941	99.03	gold quality
tendon	UBERON:0000043	98.83	gold quality
urethra	UBERON:0000057	98.82	gold quality
inferior vagus X ganglion	UBERON:0005363	98.81	gold quality
lower lobe of lung	UBERON:0008949	98.81	gold quality
mammary duct	UBERON:0001765	98.80	gold quality
visceral pleura	UBERON:0002401	98.76	gold quality
medial globus pallidus	UBERON:0002477	98.75	gold quality
vena cava	UBERON:0004087	98.72	gold quality
superficial temporal artery	UBERON:0001614	98.70	gold quality
globus pallidus	UBERON:0001875	98.69	gold quality
upper leg skin	UBERON:0004262	98.67	gold quality
tendon of biceps brachii	UBERON:0008188	98.65	gold quality
pons	UBERON:0000988	98.63	gold quality
trigeminal ganglion	UBERON:0001675	98.63	gold quality
pleura	UBERON:0000977	98.62	gold quality
saphenous vein	UBERON:0007318	98.61	gold quality
superior surface of tongue	UBERON:0007371	98.60	gold quality

Single-cell (SCXA)

Detected in 50 experiment(s), a significant marker in 45.

Experiment	Marker?	Max mean expression
E-GEOD-75140	yes	2731.77
E-CURD-7	yes	2596.33
E-CURD-6	yes	2545.07
E-ENAD-21	yes	2449.97
E-GEOD-150728	yes	1881.35
E-GEOD-93593	yes	1861.08
E-MTAB-6505	yes	1771.25
E-MTAB-11121	yes	1509.12
E-CURD-122	yes	1372.56
E-MTAB-6308	yes	1321.27
E-MTAB-9435	yes	1248.53
E-MTAB-8894	yes	1236.78
E-MTAB-10855	yes	1228.53
E-MTAB-7407	yes	1111.21
E-MTAB-7316	yes	1014.03

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

65 targets.

Target	Regulation
ABCB1	Activation
APC	Unknown
BAMBI	Repression
BCL2	Unknown
BEST1	Unknown
BIRC5	Unknown
BMP7	Repression
CCN1
CCND1	Activation
CD24	Activation
CD36	Activation
CD44	Unknown
CD74
CDH1	Unknown
CDKN1A	Unknown
CDKN1C	Activation
CDX2	Unknown
CFTR	Activation
CLDN2	Unknown
CLDN7	Repression
CLEC4C	Activation
CNTNAP2	Activation
COPS5	Activation
CXCL8	Activation
DCT	Repression
DEFA5	Unknown
DEFA6	Unknown
EIF3K
ENC1	Activation
FST	Unknown

JASPAR motifs

Motif	Name	Family
MA0830.1	TCF4	E2A
MA0830.2	TCF4	E2A
MA0830.3	TCF4	E2A

JASPAR matrix evidence (PMIDs): PMID:10594029, PMID:31081034

Upstream regulators (CollecTRI, top): BCL11A, CTNNB1, EGR1, FOXO1, FOXP1, HOXB13, HOXB1, LEF1, PAX6, PGR, RUNX3, TP53, TP63, VHL, ZIC2

miRNA regulators (miRDB)

203 targeting TCF4, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-302C-5P	99.97	72.56	3642

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• dHAND/E-protein (E2A, ME2, and ALF1) heterodimers have distinct DNA binding specificities (PMID:15351717)
• Competitive RT-PCR-based promoter activity assay showed that over-expression of ITF2B protein inhibited the expression of IL-2Ralpha gene in Jurkat cells in an NRE-dependent manner (PMID:16126178)
• haploinsufficiency of TCF4 causes PHS and suggest that D. rerio is a valuable model to study the molecular pathogenesis of Pitt-Hopkins syndrome and the role of TCF4 in brain development (PMID:17478476)
• Interstitial deletion involving TCF4 is associated with severe developmental delay and multiple abnormalities. (PMID:18222743)
• Protein sequence alignment of the closely related bHLH transcription factors ITF-2B, HeLa E box protein (HITF4), and the E2A proteins E12 and E47 revealed the presence of a highly conserved protein domain. (PMID:18371301)
• Gene disruption of TCF4 is associated with mental retardation but not always associated with Pitt-Hopkins syndrome. (PMID:18627065)
• based on results, it is proposed that the observed frequent epigenetic-mediated TCF4 silencing plays a role in tumor formation and progression (PMID:18635522)
• Nine novel deletion mutations in TCF4 in Pitt-Hopkins Syndrome are described. (PMID:18781613)
• findings suggest that the concurrent action of Spi-B and E2-2 controls the development of progenitor cells into the plasmacytoid dendritic cell lineage (PMID:18792017)
• These results identify E2-2 as a specific transcriptional regulator of the plasmacytoid dendritic cells lineage in mice and humans and reveal a key function of E proteins in the innate immune system. (PMID:18854153)
• Studies delineate an underdiagnosed mental retardation syndrome, highlighting TCF4 function during development and facilitating diagnosis within the first year of life. (PMID:19235238)
• ITF-2B is a tumor suppressor that has an important function at the adenoma to carcinoma transition. (PMID:19394332)
• This data support the notion that the ITF2 gene on chromosome 18q is a tumor suppressor gene. (PMID:19635457)
• a genotype-phenotype correlation of increased seizure activity with TCF4 missense mutations was proposed in patients with Pitt-Hopkins syndrome. (PMID:19938247)
• The diagnosis of Pitt-Hopkins syndrome, an underdiagnosed cause of mental retardation, was based on clinical and genetic findings. Searching for TCF4 mutations is highly recommended when others overlapping syndromes was excluded. (PMID:20205897)
• These data suggest that TCF4, NRXN1, and CNTNAP2 may participate in a biological pathway that is altered in patients with schizophrenia and other neuropsychiatric disorders. (PMID:20421335)
• Inactivation of TCF4 by promoter methylation is associated with the early stage of gastric carcinoma progression. (PMID:20585880)
• Data suggest that that ITF2 is one of the CXCR4 targets, which is involved in CXCR4-dependent tumor growth and invasion of breast cancer cells. (PMID:20603605)
• This study confirmed that common risk factors in the major histocompatibility complex region and TCF4 gene are associated with schizophrenia in Han Chinese. (PMID:20673877)
• A combination of genetic mapping and retroillumination photography was used to quantify the severity of the disease phenotype associated with FCD2 and to compare it to the disease characteristics of FCD1. (PMID:20811064)
• Genetic variation in TCF4 contributes to the development of Fuch’s corneal dystrophy. (PMID:20825314)
• VDM function is influenced by the TCF4 gene in schizophrenia patients. However, the elevated risk for schizophrenia is not conferred by TCF4-mediated VDM impairment. (PMID:21228604)
• The authors report the first independent replication of rs613872 conferring risk of late-onset Fuchs endothelial dystrophy (PMID:21245398)
• study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies (PMID:21533127)
• Sensorimotor gating is modulated by TCF4 genotype, indicating an influential role of TCF4 gene variations in the development of early information-processing deficits in schizophrenia. (PMID:21543597)
• Polymorphisms within TCF4, a gene which has been implicated in Fuch’s corneal dystrophy susceptibility among Europeans, was also found to be strongly associated in Chinese (PMID:21659310)
• TCF4 (+/+) individuals were only moderately developmentally delayed while TCF4 (+/-) individuals failed to reach developmental milestones beyond those typically acquired by 12 months of age. (PMID:21671075)
• these findings suggest that FAM96B acts as a regulator of E2-2 through the control of its protein expression. (PMID:21722264)
• Usage of numerous 5’ exons of the human TCF4 gene potentially yields in TCF4 protein isoforms with 18 different N-termini. (PMID:21789225)
• Common variants at TCF4 show genome-wide significant association with schizophrenia. (PMID:21791550)
• Association between schizophrenia and TCF4 is not mediated by a relatively common non-synonymous variant, or by a variant that alters mRNA expression as measured in adult human brain. (PMID:21812098)
• No obvious difference was observed between patients harboring truncating, missense mutations, or deletions, further supporting TCF4 haploinsufficiency as the molecular mechanism underlying Pitt-Hopkins syndrome. (PMID:22045651)
• We were unable to detect an association between TCF4 rs613872 genotype and the variation in corneal endothelial cell density or variation in cell morphology in a healthy young adult population. (PMID:22146553)
• variation in TCF4, genes are associated with Fuchs’ endothelial dystrophy in Caucasian Australian cases (PMID:22234156)
• report on the screening of the TCF4 and MEF2C genes in a cohort of 81 classical, atypical, and incomplete atypical Rett syndrome (RTT) patients; results suggest that these genes are not commonly associated with RTT (PMID:22383159)
• Finding suggests that sensory gating is modulated by an interaction of TCF4 genotype with smoking, and both factors may play a role in early information processing deficits also in schizophrenia. (PMID:22451930)
• different Pitt-Hopkins syndrome-associated mutations impair the functions of TCF4 by diverse mechanisms and to a varying extent, possibly contributing to the phenotypic variability of Pitt-Hopkins syndrome patients. (PMID:22460224)
• TCF4 may modulate the expression of NRXN1 and CNTNAP2 thereby defining a regulatory network in Pitt-Hopkins syndrome. (PMID:22777675)
• GPR35 shows associations in both ulcerative colitis (UC) and primary sclerosing cholangitis (PSC), whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. (PMID:22821403)
• Common TCF4 variants are involved in psychosis pathology, probably related to abnormal neurodevelopment. (PMID:22832956)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	TCF4	ENSDARG00000107408
mus_musculus	Tcf4	ENSMUSG00000053477
rattus_norvegicus	Tcf4	ENSRNOG00000012405
drosophila_melanogaster	da	FBGN0267821
caenorhabditis_elegans	hlh-2	WBGENE00001949

Paralogs (2): TCF3 (ENSG00000071564), TCF12 (ENSG00000140262)

Protein

Protein identifiers

Transcription factor 4 — P15884 (reviewed: P15884)

Alternative names: Class B basic helix-loop-helix protein 19, Immunoglobulin transcription factor 2, SL3-3 enhancer factor 2

All UniProt accessions (49): P15884, A0A075B723, A0A0D9SEK1, A0A0D9SEX8, A0A0D9SEZ3, A0A0D9SF18, A0A0D9SF97, A0A0D9SFU5, A0A0D9SFX5, A0A0D9SFZ1, A0A0D9SG44, A0A0D9SG55, A0A0D9SG61, A0A0D9SG78, A0A0D9SGE4, A0A0D9SGE5, A0A0D9SGE7, A0A0D9SGH7, A0A0D9SGJ4, A0A0E3D6N2, A0A1B0GTP2, A0A1B0GUT3, A0A1B0GV10, A0A1B0GVB8, A0A1B0GVR6, A0A1B0GW91, A0A1B0GWD5, A0A1B0GXH5, A0A6Q8PGE3, E9PH57, G0LNT4, G0LNT7, H3BMC8, H3BME8, H3BML7, H3BNI2, H3BNZ2, H3BP59, H3BPG3, H3BPJ7, H3BRF7, H3BT24, H3BT95, H3BTC3, H3BTM9, H3BTP3, H3BTZ0, H3BUQ3, K7ESI6

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5-motif. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5’-CANNTG-3’). Binds to the E-box present in the somatostatin receptor 2 initiator element (SSTR2-INR) to activate transcription. Preferentially binds to either 5’-ACANNTGT-3’ or 5’-CCANNTGG-3’.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Forms homo- or heterooligomers with myogenin. Interacts with HIVEP2. Interacts with NEUROD2. Interacts with AGBL1. Interacts with BHLHA9.

Subcellular location. Nucleus.

Tissue specificity. Expressed in adult heart, brain, placenta, skeletal muscle and to a lesser extent in the lung. In developing embryonic tissues, expression mostly occurs in the brain.

Disease relevance. Pitt-Hopkins syndrome (PTHS) [MIM:610954] A syndrome characterized by intellectual disability, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea. Features include intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, severe motor developmental delay, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. The disease is caused by variants affecting the gene represented in this entry. Corneal dystrophy, Fuchs endothelial, 3 (FECD3) [MIM:613267] A late-onset form of Fuchs endothelial corneal dystrophy, a disease caused by loss of endothelium of the central cornea. It is characterized by focal wart-like guttata that arise from Descemet membrane and develop in the central cornea, epithelial blisters, reduced vision and pain. Descemet membrane is thickened by abnormal collagenous deposition. The disease is caused by variants affecting the gene represented in this entry. Causative mutations are heterozygous TCF4 intronic trinucleotide repeat expansions (CTG)n. Defects in TCF4 may cause autosomal dominant symmetrical acral keratoderma (SAK)syndrome. Symmetrical acral keratodermadefines is characterized by brown/black hyperkeratotic patches symmetrically distributed on the acral regions, especially the wrists, ankles, dorsa of hands, fingers and feet affects young and middle aged men. Patients have epidermis thickened by acanthosis and compact stratum corneum.

Domain organisation. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.

Isoforms (16)

UniProt ID	Names	Canonical?
P15884-1	SEF2-1B, B-	yes
P15884-2	SEF2-1A, A+
P15884-3	SEF2-1D, B+
P15884-4	B+delta
P15884-5	B-delta
P15884-6	A-
P15884-7	G-
P15884-8	H-
P15884-9	D-
P15884-10	F-
P15884-11	11
P15884-12	E-
P15884-13	13
P15884-14	C-
P15884-15	C-delta
P15884-16	I-

RefSeq proteins (46): NP_001077431, NP_001230155, NP_001230156, NP_001230157, NP_001230159, NP_001230160, NP_001230161, NP_001230162, NP_001230163, NP_001230164, NP_001230165, NP_001293136, NP_001293137, NP_001317533, NP_001317534, NP_001335140, NP_001335141, NP_001335142, NP_001335143, NP_001335144, NP_001335145, NP_001335146, NP_001335147, NP_001335148, NP_001335149, NP_001356496, NP_001356497, NP_001356498, NP_001356499, NP_001356500, NP_001356501, NP_001356502, NP_001356503, NP_001356504, NP_001356505, NP_001356506, NP_001356507, NP_001356508, NP_001356509, NP_001356510, NP_001356511, NP_001356512, NP_001356513, NP_001356514, NP_001356515, NP_003190 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR051098	NeuroDiff_E-box_TFs	Family

Pfam: PF00010

Enzyme classification (BRENDA):

• EC 7.6.2.3 — ABC-type glutathione-S-conjugate transporter (BRENDA: 8 organisms, 145 substrates, 63 inhibitors, 16 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0865–0.91	5
MONOMETHYLARSONOUS ACID DIGLUTATHIONE[SIDE 1]	0.023–0.033	4
S-(2,4-DINITROPHENYL)GLUTATHIONE[SIDE 1]	0.0141–0.032	2
S-(LEUKOTRIENE C4)GLUTATHIONE[SIDE 1]	0.0001	2
4-(GLUTATHIONE-S-YL)-QUINOLINE-1-OXIDE[SIDE 1]	0.0095	1
ARSENIC TRIGLUTATHIONE[SIDE 1]	0.0003	1
S-GLUTATHIONE[SIDE 1]	12	1

UniProt features (67 total): splice variant 18, sequence variant 16, compositionally biased region 11, region of interest 8, modified residue 5, sequence conflict 3, helix 3, chain 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6OD3	X-RAY DIFFRACTION	1.49
6OD4	X-RAY DIFFRACTION	1.7
6OD5	X-RAY DIFFRACTION	2.05
8OSB	X-RAY DIFFRACTION	2.9
2KWF	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15884-F1	52.08	0.13

Functional residue map

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

Post-translational modifications (5): 66, 87, 92, 372, 515

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-525793	Myogenesis
R-HSA-9839394	TGFBR3 expression
R-HSA-9943411	CHD1 and CHD2 subfamily
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-9006936	Signaling by TGFB family members
R-HSA-9839373	Signaling by TGFBR3

MSigDB gene sets: 883 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, RRAGTTGT_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOZGIT_ESR1_TARGETS_DN, VICENT_METASTASIS_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, MODULE_493, GOBP_NEUROGENESIS, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, YY1_Q6, PATIL_LIVER_CANCER, NKX61_01, SENESE_HDAC1_AND_HDAC2_TARGETS_DN

GO Biological Process (7): regulation of transcription by RNA polymerase II (GO:0006357), nervous system development (GO:0007399), cell differentiation (GO:0030154), positive regulation of neuron differentiation (GO:0045666), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), protein-DNA complex assembly (GO:0065004)

GO Molecular Function (13): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), TFIIB-class transcription factor binding (GO:0001093), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), beta-catenin binding (GO:0008013), identical protein binding (GO:0042802), protein heterodimerization activity (GO:0046982), E-box binding (GO:0070888), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667), beta-catenin-TCF7L2 complex (GO:0070369), beta-catenin-TCF complex (GO:1990907)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Developmental Biology	1
Signaling by TGFBR3	1
CHD chromatin remodelers	1
TCF dependent signaling in response to WNT	1
Signal Transduction	1
Signaling by TGFB family members	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
protein binding	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
system development	1
cellular developmental process	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
protein-containing complex assembly	1
protein-DNA complex organization	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
RNA polymerase II general transcription initiation factor binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
protein dimerization activity	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1
protein-containing complex	1
catenin-TCF7L2 complex	1
beta-catenin-TCF complex	1
RNA polymerase II transcription regulator complex	1

Protein interactions and networks

STRING

2198 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TCF4	CTNNB1	P35222	993
TCF4	MYOD1	P15172	910
TCF4	POU5F1	P31359	835
TCF4	COL8A2	P25067	766
TCF4	ID2	Q02363	761
TCF4	ID1	P41134	759
TCF4	SLC4A11	Q8NBS3	755
TCF4	SOX2	P48431	753
TCF4	NANOG	Q9H9S0	735
TCF4	NEUROD1	Q13562	717
TCF4	SRY	Q05066	706
TCF4	TRIB3	Q96RU7	680
TCF4	KLF4	P78338	673
TCF4	HIVEP2	P31629	668
TCF4	PPARG	P37231	665

IntAct

590 interactions, top by confidence:

A	B	Type	Score
TCF4	SGF29	psi-mi:“MI:0915”(physical association)	0.840
TCF4	ID3	psi-mi:“MI:0915”(physical association)	0.800
TWIST2	TCF4	psi-mi:“MI:0915”(physical association)	0.740
TCF4	NEUROG1	psi-mi:“MI:0915”(physical association)	0.740
TCF4	FERD3L	psi-mi:“MI:0915”(physical association)	0.740
TCF4	CABP5	psi-mi:“MI:0915”(physical association)	0.740
TCF4	BCAS2	psi-mi:“MI:0915”(physical association)	0.670
CDKN2C	TCF4	psi-mi:“MI:0915”(physical association)	0.670
HAND2	TCF4	psi-mi:“MI:0915”(physical association)	0.670
TCF4	TAL2	psi-mi:“MI:0915”(physical association)	0.670
PLEKHN1	TCF4	psi-mi:“MI:0915”(physical association)	0.670
EFHC1	TCF4	psi-mi:“MI:0915”(physical association)	0.670
LGALS14	TCF4	psi-mi:“MI:0915”(physical association)	0.670
TCF4	DEF6	psi-mi:“MI:0915”(physical association)	0.670
TCF4	GORASP2	psi-mi:“MI:0915”(physical association)	0.670
TCF4	NEK6	psi-mi:“MI:0915”(physical association)	0.670
TXNL4B	TCF4	psi-mi:“MI:0915”(physical association)	0.670
TCF4	NDOR1	psi-mi:“MI:0915”(physical association)	0.670
OSGIN1	TCF4	psi-mi:“MI:0915”(physical association)	0.670
TCF4	EXOSC1	psi-mi:“MI:0915”(physical association)	0.670
TCF4	HAND2	psi-mi:“MI:0915”(physical association)	0.670
TCF4	PLEKHN1	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (554): TCF4 (Affinity Capture-Western), CTNNB1 (Affinity Capture-Western), TCF4 (Affinity Capture-Western), TCF4 (Two-hybrid), TCF4 (Two-hybrid), TCF4 (Two-hybrid), TCF4 (Two-hybrid), TCF4 (Two-hybrid), TCF4 (Two-hybrid), TCF4 (Two-hybrid), TCF4 (Two-hybrid), TCF4 (Two-hybrid), TCF4 (Two-hybrid), TCF4 (Two-hybrid), TCF4 (Two-hybrid)

ESM2 similar proteins: A0A087WPF7, A0A0R4IBL7, O09000, O54972, O70305, O75081, O75376, P15806, P15881, P15884, P15923, P21677, P30985, P51514, P98180, Q05AQ8, Q14157, Q14687, Q1LY51, Q2VPM4, Q3U3C9, Q4KKX4, Q4VCS5, Q566L4, Q5F3B1, Q5SFM8, Q5T6F2, Q60722, Q60974, Q61286, Q62655, Q6DIH5, Q7ZWN6, Q7ZXS3, Q80X50, Q86YP4, Q8BZ47, Q8CHY6, Q8IXK0, Q8VHG2

Diamond homologs: A0A0R4IBL7, G5EEG9, P11420, P15806, P15881, P15884, P15923, P21677, P30985, P51514, P98180, Q01978, Q28772, Q60420, Q60722, Q61286, Q62655, Q90683, Q91605, Q99081

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
JUN	up-regulates	TCF4	binding
CTNNB1	“up-regulates activity”	TCF4	binding
TCF4	“form complex”	MYOD/E2-2	binding
NLK	down-regulates	TCF4	phosphorylation
TCF4	“up-regulates quantity by expression”	SOX9	“transcriptional regulation”
TCF4	“up-regulates quantity by expression”	MYC	“transcriptional regulation”
HOXB13	“down-regulates quantity by repression”	TCF4	“transcriptional regulation”
TCF4	“up-regulates quantity by expression”	CCND1	“transcriptional regulation”
TCF4	“up-regulates quantity by expression”	ABCB1	“transcriptional regulation”
TCF4	“up-regulates quantity by expression”	CNTNAP2	“transcriptional regulation”
TCF4	“up-regulates quantity by expression”	NRXN1	“transcriptional regulation”
FOXO1	“down-regulates activity”	TCF4	binding
ID2	“down-regulates activity”	TCF4	binding
ID3	“down-regulates activity”	TCF4	binding
ID1	“down-regulates activity”	TCF4	binding
TCF4	“up-regulates quantity by expression”	SSTR2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of protein catabolic process	5	16.4×	1e-02

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 2 cancer types — MBL, PAST.

Clinical variants and AI predictions

ClinVar

1196 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	173
Likely pathogenic	92
Uncertain significance	411
Likely benign	336
Benign	101

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069805	NM_001083962.2(TCF4):c.1505dup (p.Gln504fs)	Pathogenic
1072137	NM_001083962.2(TCF4):c.1504C>T (p.Gln502Ter)	Pathogenic
1072183	NM_001083962.2(TCF4):c.1171G>T (p.Glu391Ter)	Pathogenic
1074252	NC_000018.9:g.(?_52888562)_53256860del	Pathogenic
1076549	NM_001083962.2(TCF4):c.770dup (p.His258fs)	Pathogenic
1174496	NM_001083962.2(TCF4):c.677del (p.Pro226fs)	Pathogenic
1199893	NM_001083962.2(TCF4):c.1831C>G (p.Leu611Val)	Pathogenic
1208406	NM_001083962.2(TCF4):c.1849G>A (p.Val617Ile)	Pathogenic
1320266	NM_001083962.2(TCF4):c.990+1G>T	Pathogenic
1326873	Single allele	Pathogenic
1339574	NM_001083962.2(TCF4):c.1249del (p.Asp417fs)	Pathogenic
1355508	NM_001083962.2(TCF4):c.1135_1138dup (p.His380fs)	Pathogenic
1412517	NM_001083962.2(TCF4):c.188del (p.Gly63fs)	Pathogenic
1423223	NM_001083962.2(TCF4):c.622_628dup (p.Thr210fs)	Pathogenic
1451556	NM_001083962.2(TCF4):c.670del (p.Ser224fs)	Pathogenic
1458548	NC_000018.9:g.(?52921708)(53070769_?)del	Pathogenic
1459978	NC_000018.9:g.(?53070665)(53070769_?)del	Pathogenic
160076	NM_001083962.2(TCF4):c.1146+1G>A	Pathogenic
160078	NM_001083962.2(TCF4):c.1498G>T (p.Gly500Ter)	Pathogenic
160085	NM_001083962.2(TCF4):c.469C>T (p.Arg157Ter)	Pathogenic
160087	NM_001083962.2(TCF4):c.656-1G>C	Pathogenic
160092	NM_001083962.2(TCF4):c.990G>A (p.Ser330=)	Pathogenic
160093	NM_001083962.2(TCF4):c.991-2A>G	Pathogenic
167726	NM_001083962.2(TCF4):c.1414del (p.Val472fs)	Pathogenic
167729	NM_001083962.2(TCF4):c.655+1G>T	Pathogenic
1686251	NM_001083962.2(TCF4):c.1699_1701del (p.Lys567del)	Pathogenic
1686252	NM_001083962.2(TCF4):c.1486G>A (p.Gly496Ser)	Pathogenic
1686254	NM_001083962.2(TCF4):c.327C>A (p.Tyr109Ter)	Pathogenic
1703506	NM_001083962.2(TCF4):c.1879+1G>T	Pathogenic
1706459	NM_001243226.3(TCF4):c.286+1G>A	Pathogenic

SpliceAI

4611 predictions. Top by Δscore:

Variant	Effect	Δscore
18:55228842:CTGA:C	donor_loss	1.0000
18:55228843:TGA:T	donor_loss	1.0000
18:55228844:GAC:G	donor_loss	1.0000
18:55228845:ACC:A	donor_loss	1.0000
18:55228846:CCTCG:C	donor_loss	1.0000
18:55229072:TATTG:T	acceptor_gain	1.0000
18:55229073:ATTG:A	acceptor_gain	1.0000
18:55229074:TTG:T	acceptor_gain	1.0000
18:55229075:TG:T	acceptor_gain	1.0000
18:55229077:C:CC	acceptor_gain	1.0000
18:55229077:CT:C	acceptor_loss	1.0000
18:55229078:T:A	acceptor_loss	1.0000
18:55232672:C:CA	acceptor_loss	1.0000
18:55232672:C:CC	acceptor_gain	1.0000
18:55232673:T:C	acceptor_loss	1.0000
18:55254493:TTA:T	donor_loss	1.0000
18:55254494:TA:T	donor_loss	1.0000
18:55254495:A:AC	donor_gain	1.0000
18:55254495:A:AG	donor_loss	1.0000
18:55254495:AC:A	donor_gain	1.0000
18:55254496:C:CC	donor_gain	1.0000
18:55254496:CC:C	donor_gain	1.0000
18:55254496:CCAT:C	donor_gain	1.0000
18:55254696:CTTTG:C	acceptor_gain	1.0000
18:55254697:TTTG:T	acceptor_gain	1.0000
18:55254698:TTG:T	acceptor_gain	1.0000
18:55254699:TG:T	acceptor_gain	1.0000
18:55254699:TGCT:T	acceptor_loss	1.0000
18:55254701:C:CC	acceptor_gain	1.0000
18:55254702:T:A	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000405 (18:55407503 T>C), RS1000002495 (18:55311043 C>G,T), RS1000005507 (18:55628039 G>A), RS1000009211 (18:55319995 G>C), RS1000019584 (18:55501320 C>A,T), RS1000026293 (18:55405699 T>C), RS1000029380 (18:55558194 G>C), RS1000030733 (18:55577140 A>G,T), RS1000031978 (18:55545349 G>A), RS1000032983 (18:55582029 T>C), RS1000039195 (18:55295776 G>A), RS1000045070 (18:55536937 A>G,T), RS1000050808 (18:55274046 C>T), RS1000057865 (18:55222648 A>G), RS1000058766 (18:55412903 T>C)

Disease associations

OMIM: gene MIM:602272 | disease phenotypes: MIM:610954, MIM:613267, MIM:182601

GenCC curated gene-disease

Disease	Classification	Inheritance
Pitt-Hopkins syndrome	Definitive	Autosomal dominant
corneal dystrophy, Fuchs endothelial, 3	Strong	Autosomal dominant
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant
Fuchs’ endothelial dystrophy	Supportive	Autosomal dominant
intellectual disability	Limited	Autosomal dominant
autism spectrum disorder	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Pitt-Hopkins syndrome	Definitive	AD

Mondo (12): Pitt-Hopkins syndrome (MONDO:0012589), corneal dystrophy, Fuchs endothelial, 3 (MONDO:0013203), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071), hereditary spastic paraplegia 4 (MONDO:0008438), stereotypic movement disorder (MONDO:0002265), esophageal atresia (MONDO:0001044), pyloric stenosis (MONDO:0001561), microcephaly (MONDO:0001149), neurodevelopmental disorder (MONDO:0700092), autosomal dominant non-syndromic intellectual disability (MONDO:0015802), Fuchs’ endothelial dystrophy (MONDO:0005321)

Orphanet (5): Pitt-Hopkins syndrome (Orphanet:2896), Fuchs endothelial corneal dystrophy (Orphanet:98974), Autosomal dominant spastic paraplegia type 4 (Orphanet:100985), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0002032	Esophageal atresia
HP:0002021	Pyloric stenosis
HP:0000252	Microcephaly

GWAS associations

128 associations (top):

Study	Trait	p-value
GCST000434_1	Schizophrenia	1.000000e-07
GCST000435_3	Schizophrenia	4.000000e-09
GCST000790_2	Fuchs’s corneal dystrophy	1.000000e-18
GCST001017_3	Diabetic retinopathy	3.000000e-06
GCST001242_9	Schizophrenia	1.000000e-06
GCST001565_2	Schizophrenia	1.000000e-07
GCST001615_1	Sclerosing cholangitis and ulcerative colitis (combined)	3.000000e-08
GCST001851_4	Schizophrenia	3.000000e-10
GCST001877_5	Autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia (combined)	2.000000e-07
GCST001957_12	Obesity (early onset extreme)	4.000000e-06
GCST002149_17	Schizophrenia	1.000000e-08
GCST002539_87	Schizophrenia	3.000000e-12
GCST002539_88	Schizophrenia	2.000000e-11
GCST003264_459	Post bronchodilator FEV1/FVC ratio	3.000000e-06
GCST003989_20	Chin dimples	7.000000e-15
GCST004217_6	Fuchs’s corneal dystrophy	3.000000e-200
GCST004521_159	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_220	Autism spectrum disorder or schizophrenia	5.000000e-11
GCST004521_52	Autism spectrum disorder or schizophrenia	9.000000e-10
GCST004521_99	Autism spectrum disorder or schizophrenia	1.000000e-09
GCST004946_122	Schizophrenia	5.000000e-12
GCST005170_2	Intraocular pressure	2.000000e-15
GCST005235_16	Hand grip strength	6.000000e-08
GCST005580_223	Intraocular pressure	6.000000e-20
GCST005580_234	Intraocular pressure	5.000000e-17
GCST005787_6	Heart rate response to exercise	4.000000e-09
GCST005829_13	Hand grip strength	2.000000e-12
GCST005830_19	Hand grip strength	6.000000e-15
GCST005839_21	Depression	4.000000e-11
GCST006083_9	Prostate cancer (advanced)	5.000000e-06

EFO canonical traits (34, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0004695	intraocular pressure measurement
EFO:0006941	grip strength measurement
EFO:0009184	heart rate response to exercise
EFO:0004285	albuminuria
EFO:0004778	self rated health
EFO:0006336	diastolic blood pressure
EFO:0007006	depressive symptom measurement
EFO:0007660	neuroticism measurement
EFO:0007869	wellbeing measurement
EFO:0008579	risk-taking behaviour
EFO:0009592	social interaction measurement
EFO:0007865	loneliness measurement
EFO:0009594	irritability measurement
EFO:0008475	mood instability measurement
EFO:0009588	feeling “fed-up” measurement
EFO:0009589	worry measurement
EFO:0009270	heel bone mineral density
EFO:0006335	systolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0008328	chronotype measurement
EFO:0010067	corneal resistance factor
EFO:0010066	corneal hysteresis
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0010091	tea consumption measurement
EFO:0010130	health study participation
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0007778	urinary albumin to creatinine ratio
EFO:0009695	household income

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D004933	Esophageal Atresia	C06.198.330; C06.405.117.260; C16.131.314.330
D005642	Fuchs’ Endothelial Dystrophy	C11.204.236.438; C11.270.162.438; C16.320.290.162.410
D017219	Gastric Outlet Obstruction	C06.405.748.340
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D011707	Pyloric Stenosis	C06.405.748.340.690
D019956	Stereotypic Movement Disorder	F03.625.984
C567678	Corneal Dystrophy, Fuchs Endothelial, 3 (supp.)
C537403	Pitt-Hopkins syndrome (supp.)
C536865	Spastic paraplegia 4, autosomal dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3885541 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 6,527 (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
CHEMBL1208572	SALINOMYCIN	2	6,527

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Basic helix-loop-helix (BHLH) TFs

Binding affinities (BindingDB)

48 measured of 78 human assays (78 total across all organisms); most potent 48 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-(4-chlorophenoxy)-N-[3-[5-[(4-chlorophenoxy)methyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
N-[3-[3-[(4-chlorophenoxy)methyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]-2-(4-methylphenoxy)acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[3-[(4-chlorophenoxy)methyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-2-fluorophenoxy)-N-[3-[3-[(4-chlorophenoxy)methyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[[6-(trifluoromethyl)-3-pyridinyl]oxy]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[[5-(trifluoromethyl)-3-pyridinyl]oxy]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[(6-methoxy-3-pyridinyl)oxy]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[(6-cyclopropyl-3-pyridinyl)oxy]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[[5-(trifluoromethyl)-3-pyridinyl]oxymethyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-(4-methylphenoxy)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-(3-cyanophenoxy)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-(3,4-dimethylphenoxy)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-(3-methylphenoxy)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-(3-methoxyphenoxy)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-(2-fluorophenoxy)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[(5-fluoro-3-pyridinyl)oxymethyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[[6-(trifluoromethyl)-3-pyridinyl]oxymethyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[(5-chloro-6-methyl-3-pyridinyl)oxymethyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[(5-chloro-3-pyridinyl)oxymethyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[3-[[5-(trifluoromethyl)-3-pyridinyl]oxymethyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[3-[[2-(trifluoromethyl)-4-pyridinyl]oxymethyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[3-[[6-(trifluoromethyl)-3-pyridinyl]oxymethyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[3-[[5-chloro-6-(trifluoromethyl)-3-pyridinyl]oxymethyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-hydroxy-4-[3-[[2-(trifluoromethyl)-4-pyridinyl]oxymethyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[2.2.2]octanyl]acetamide	EC50	20 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-methylphenoxy)-N-[3-[3-[(4-chlorophenoxy)methyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(3-chlorophenoxy)-N-[3-[3-[(4-chlorophenoxy)methyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
N-[3-[3-[(4-chlorophenoxy)methyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]-2-(3-fluorophenoxy)acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
N-[3-[3-[(4-chlorophenoxy)methyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]-2-(4-fluorophenoxy)acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
N-[3-[3-[(4-chlorophenoxy)methyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]-2-[[6-(trifluoromethyl)-3-pyridinyl]oxy]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[(6-cyano-5-methyl-3-pyridinyl)oxy]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[(6-cyano-3-pyridinyl)oxy]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-(4-methoxyphenoxy)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-(2-chlorophenoxy)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-(2-methylphenoxy)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-(3-fluorophenoxy)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[(5-methyl-3-pyridinyl)oxymethyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[(6-methyl-3-pyridinyl)oxymethyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[(6-methoxy-5-methyl-3-pyridinyl)oxymethyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[5-[(6-cyano-3-pyridinyl)oxymethyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-[3-[(6-cyclopropyl-3-pyridinyl)oxymethyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[1.1.1]pentanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[4-[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]-3-oxo-1-bicyclo[2.2.2]octanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-hydroxy-4-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]-1-bicyclo[2.2.2]octanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
2-(4-chloro-3-fluorophenoxy)-N-[3-hydroxy-4-[3-[[6-(trifluoromethyl)-3-pyridinyl]oxymethyl]-1,2,4-oxadiazol-5-yl]-1-bicyclo[2.2.2]octanyl]acetamide	EC50	65 nM	US-20250115563: MODULATORS OF THE INTEGRATED STRESS PATHWAY
CHEMBL5417142	IC50	2570 nM
[(2R)-1-[3,10-dihydroxy-12-[(2R)-2-(4-hydroxyphenoxy)carbonyloxypropyl]-2,6,7,11-tetramethoxy-4,9-dioxoperylen-1-yl]propan-2-yl] benzoate	KI	53800 nM	US-9284299: Substituted 1H-indazol-1-ol analogs as inhibitors of beta catenin/Tcf protein-protein interactions
CHEBI:3556	KI	62500 nM	US-9284299: Substituted 1H-indazol-1-ol analogs as inhibitors of beta catenin/Tcf protein-protein interactions
1-hydroxy-5-[2-(2H-tetrazol-5-yl)ethyl]benzotriazole	KI	171000 nM	US-9284299: Substituted 1H-indazol-1-ol analogs as inhibitors of beta catenin/Tcf protein-protein interactions
1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione	KI	171000 nM	US-9284299: Substituted 1H-indazol-1-ol analogs as inhibitors of beta catenin/Tcf protein-protein interactions

ChEMBL bioactivities

46 potent at pChembl≥5 of 53 total, top 39 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.80	IC50	16	nM	CHEMBL5285550
6.82	IC50	150	nM	CHEMBL5274107
6.35	Kd	450	nM	CHEMBL254381
6.28	IC50	530	nM	CHEMBL5436013
6.23	IC50	583	nM	CHEMBL5189621
6.19	IC50	640	nM	CHEMBL3780110
6.19	Ki	640	nM	CHEMBL4451478
6.19	IC50	640	nM	CHEMBL2397074
6.10	IC50	800	nM	CHEMBL578512
5.87	Ki	1360	nM	CHEMBL5191974
5.87	Ki	1360	nM	CHEMBL3260853
5.82	IC50	1500	nM	CHEMBL5278981
5.78	IC50	1650	nM	CHEMBL5185515
5.77	IC50	1700	nM	CHEMBL1214274
5.74	IC50	1820	nM	CHEMBL5185515
5.64	IC50	2300	nM	CHEMBL5173483
5.62	IC50	2400	nM	CHEMBL179197
5.59	IC50	2570	nM	CHEMBL5417142
5.59	IC50	2590	nM	CHEMBL5417142
5.58	IC50	2630	nM	CHEMBL5417142
5.52	IC50	3000	nM	CHEMBL2312139
5.50	IC50	3200	nM	CHEMBL261214
5.50	Ki	3140	nM	CHEMBL2323032
5.41	IC50	3860	nM	SALINOMYCIN
5.40	IC50	4000	nM	CHEMBL5172034
5.39	IC50	4100	nM	CHEMBL2397075
5.39	IC50	4100	nM	CHEMBL5397220
5.38	IC50	4200	nM	CHEMBL5284392
5.36	IC50	4400	nM	CHEMBL2312139
5.32	IC50	4800	nM	CHEMBL5202327
5.14	Ki	7240	nM	CHEMBL3943439
5.06	IC50	8700	nM	CERCOSPORIN
5.06	IC50	8700	nM	CHEMBL2323033
5.02	IC50	9500	nM	CHEMBL5432489
5.00	IC50	1e+04	nM	CHEMBL2323033
5.00	IC50	1e+04	nM	CHEMBL3890384
5.00	IC50	1e+04	nM	CHEMBL5192638
5.00	IC50	1e+04	nM	CHEMBL261214
5.00	IC50	1e+04	nM	CHEMBL5397220

PubChem BioAssay actives

46 with measured affinity, of 55 total; 32 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
6-[4-[2-(diethylamino)ethoxy]phenyl]-3,8-dimethylpteridine-2,4-dione	1958858: Inhibition of beta catenin/Tcf4 (unknown origin) protein protein interaction	ic50	0.0160	uM
[4-[[(6S,9S,9aS)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)-3,6,9,9a-tetrahydropyrazino[2,1-c][1,2,4]triazin-6-yl]methyl]phenyl] dihydrogen phosphate	1979670: Inhibition of beta-Catenin/TCF4 (unknown origin) protein-protein interaction	ic50	0.1500	uM
N-[(E)-(5-methylfuran-2-yl)methylideneamino]-2-phenoxybenzamide	1288067: Inhibition of His6 tagged Tcf4 1-53/beta catenin (unknown origin) interaction by VP-ITC titration calorimeter method	kd	0.4500	uM
methyl 3-[(4-methoxyphenyl)sulfonylamino]benzoate	1979701: Inhibition of beta-Catenin (301 to 670 residues)/TCF4 protein-protein interaction in human HCT-116 cells incubated for 20 hrs by TOPFLASH luciferase reporter assay	ic50	0.5300	uM
methyl 3-[(4-methylphenyl)sulfonylamino]benzoate	1979701: Inhibition of beta-Catenin (301 to 670 residues)/TCF4 protein-protein interaction in human HCT-116 cells incubated for 20 hrs by TOPFLASH luciferase reporter assay	ic50	0.5830	uM
methyl (6R,6aS,14aS)-1,6,8,14a-tetrahydroxy-11-[[(3S,4S,5S,6R)-4-hydroxy-3,5-dimethoxy-6-methyloxan-2-yl]amino]-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6-dihydrobenzo[a]tetracene-2-carboxylate	1288068: Inhibition of human GST tagged Tcf4/beta catenin interaction after 2 hrs using fluorescent AP Attophos substrate by ELISA analysis	ic50	0.6400	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[(5-chloro-1H-indole-2-carbonyl)amino]-3-naphthalen-2-ylpropanoyl]amino]-3-(2H-tetrazol-5-yl)propanoyl]amino]-5-oxo-5-[4-(trifluoromethoxy)anilino]pentanoic acid	1933361: Inhibition of beta catenin/Tcf4 (unknown origin) assessed as inhibition constant	ki	0.6400	uM
methyl (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-[[(2R,3S,4S,5S,6R)-4-hydroxy-3,5-dimethoxy-6-methyloxan-2-yl]amino]-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6-dihydrobenzo[a]tetracene-2-carboxylate	1979676: Inhibition of human beta-Catenin/GST-tagged TCF4 (unknown origin) protein-protein interaction incubated for 2 hrs by ELISA assay	ic50	0.6400	uM
1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	1288068: Inhibition of human GST tagged Tcf4/beta catenin interaction after 2 hrs using fluorescent AP Attophos substrate by ELISA analysis	ic50	0.8000	uM
(4S)-4-[[(2S)-3-carboxy-2-[[(2S)-2-[(5-chloro-1H-indole-3-carbonyl)amino]-3-naphthalen-2-ylpropanoyl]amino]propanoyl]amino]-5-methoxy-5-oxopentanoic acid	1869131: Binding affinity to beta-catenin (142 to 686 residues) (unknown origin)/C-terminal fluorescein-labeled human Tcf4 (7 to 51 residues) assessed as inhibition constant by fluorescence polarization competitive assay	ki	1.3600	uM
(4S)-4-[[(2S)-3-carboxy-2-[[(2S)-2-[[2-(5-chloro-1H-indol-2-yl)acetyl]amino]-3-naphthalen-2-ylpropanoyl]amino]propanoyl]amino]-5-methoxy-5-oxopentanoic acid	1979691: Inhibition of wild type beta-Catenin (142 to 686 residues) (unknown origin)/C-terminal fluorescein-labeled human TCF4 (7 to 51 residues) protein-protein interaction assessed as inhibition constant incubated for 30 mins by fluorescence polarization assay	ki	1.3600	uM
(Z)-3-chloro-2,3-bis(4-methoxyphenyl)prop-2-enal	1924301: Inhibition of beta catenin/Tcf4 (unknown origin) protein protein interaction measured after 24 hrs by TOP-flash luciferase reporter gene assay	ic50	1.5000	uM
4-[(E)-3-phenylprop-2-enyl]-N-(4-sulfamoylphenyl)piperazine-1-carbothioamide	1979685: Inhibition of human GST-tagged beta-Catenin/human His-tagged N-terminal biotinylated TCF4 (8 to 53 residues) protein-protein interaction by AlphaScreen assay	ic50	1.6500	uM
4-[(3-chloro-1,4-dioxonaphthalen-2-yl)amino]-N-pyridin-2-ylbenzenesulfonamide	1850543: Inhibition of beta catenin/Tcf4 (8 to 30 reisdues) (unknown origin) incubated for 3 hrs by fluorescence polarisation assay	ic50	1.7000	uM
4-(6-fluoro-1H-benzimidazol-2-yl)-N,N-dimethylaniline	1850545: Inhibition of beta catenin/Tcf4 (unknown origin) protein protein interaction measured after 24 hrs by TOP-flash luciferase reporter gene assay	ic50	2.3000	uM
3-butanoyl-1,8-dihydroxy-2-methylphenanthrene-9,10-dione	1288068: Inhibition of human GST tagged Tcf4/beta catenin interaction after 2 hrs using fluorescent AP Attophos substrate by ELISA analysis	ic50	2.4000	uM
disodium;[4-[[(6S,9aS)-1-(benzylcarbamoyl)-8-(2,3-dihydrocinnolin-8-ylmethyl)-4,7-dioxo-2-prop-2-enyl-3,6,9,9a-tetrahydropyrazino[2,1-c][1,2,4]triazin-6-yl]methyl]phenyl] phosphate	1979671: Inhibition of beta-Catenin/TCF4 protein-protein interaction in human Hep3B cells	ic50	2.5700	uM
(6S,9aS)-N-benzyl-6-[(4-hydroxyphenyl)methyl]-8-(naphthalen-1-ylmethyl)-4,7-dioxo-3,6,9,9a-tetrahydro-2H-pyrazino[1,2-a]pyrimidine-1-carboxamide	1924301: Inhibition of beta catenin/Tcf4 (unknown origin) protein protein interaction measured after 24 hrs by TOP-flash luciferase reporter gene assay	ic50	3.0000	uM
1-hydroxy-5-[2-(2H-tetrazol-5-yl)ethyl]indazole	1979691: Inhibition of wild type beta-Catenin (142 to 686 residues) (unknown origin)/C-terminal fluorescein-labeled human TCF4 (7 to 51 residues) protein-protein interaction assessed as inhibition constant incubated for 30 mins by fluorescence polarization assay	ki	3.1400	uM
1-[3,10-dihydroxy-12-[2-(4-hydroxyphenoxy)carbonyloxypropyl]-2,6,7,11-tetramethoxy-4,9-dioxoperylen-1-yl]propan-2-yl benzoate	1288068: Inhibition of human GST tagged Tcf4/beta catenin interaction after 2 hrs using fluorescent AP Attophos substrate by ELISA analysis	ic50	3.2000	uM
Salinomycin	1979674: Inhibition of beta-Catenin/TCF4 protein-protein interaction in human HEK293T cells incubated for 24 hrs by RT-PCR analysis	ic50	3.8600	uM
2-[(3S,6S,9S,12S,15S,25S,28S,31S,34S,37S,40S,46S)-23-(2-amino-2-oxoethyl)-12-(3-amino-3-oxopropyl)-25-benzyl-34-[[(2-bromoacetyl)amino]methyl]-31-[(2S)-butan-2-yl]-37-(carboxymethyl)-6-[3-(diaminomethylideneamino)propyl]-9,15,28-tris[(1R)-1-hydroxyethyl]-3-methyl-2,5,8,11,14,17,24,27,30,33,36,39,42,45-tetradecaoxo-20-thia-1,4,7,10,13,16,23,26,29,32,35,38,41,44-tetradecazabicyclo[44.3.0]nonatetracontan-40-yl]acetic acid	1856138: Binding affinity to FITC-labeled Tcf4 (unknown origin) /6His-tagged beta-catenin (135 to 668 residues) (unknown origin) protein-protein interaction assessed as inhibition constant by fluorescence polarization assay	ic50	4.0000	uM
1-[12-[2-(2,4-dihydroxy-6-methylbenzoyl)oxypropyl]-3,10-dihydroxy-2,6,7,11-tetramethoxy-4,9-dioxoperylen-1-yl]propan-2-yl 4-hydroxy-2,6-dimethylbenzoate	1979676: Inhibition of human beta-Catenin/GST-tagged TCF4 (unknown origin) protein-protein interaction incubated for 2 hrs by ELISA assay	ic50	4.1000	uM
1-[12-[2-(2,4-dihydroxy-6-methylbenzoyl)oxypropyl]-3,10-dihydroxy-2,6,7,11-tetramethoxy-4,9-dioxoperylen-1-yl]propan-2-yl 2,4-dihydroxy-6-methylbenzoate	1288068: Inhibition of human GST tagged Tcf4/beta catenin interaction after 2 hrs using fluorescent AP Attophos substrate by ELISA analysis	ic50	4.1000	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[(6S,9S,12S,15S,18R)-6-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-12-(3-amino-3-oxopropyl)-9-(2-carboxyethyl)-15-(2-methylpropyl)-7,10,13,16-tetraoxo-1,8,11,14,17,21,22-heptazabicyclo[18.2.1]tricosa-20(23),21-diene-18-carbonyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(6S,9S,12S,15S,18R)-18-[[(2S,3S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]-15-(3-carbamimidamidopropyl)-9-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-7,10,13,16-tetraoxo-1,8,11,14,17,21,22-heptazabicyclo[18.2.1]tricosa-20(23),21-dien-6-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1924302: Inhibition of beta-catenin/Tcf4 (unknown origin) in human SW480 cells assessed as reduction in cyclin D1 level qRT-PCR analysis	ic50	4.2000	uM
2-[(1R,4S,7S,10S,13S,24S,27S,30S,33S,36R,39S,45S,51S,54S)-33-(2-amino-2-oxoethyl)-13-benzyl-30-[3-(diaminomethylideneamino)propyl]-27-[(1R)-1-hydroxyethyl]-4,7-bis(2-methylpropyl)-2,5,8,11,14,18,22,25,28,31,34,37,40,46,52,55-hexadecaoxo-10,24,39-tri(propan-2-yl)-58,66-dithia-3,6,9,12,15,19,23,26,29,32,35,38,41,47,53,56-hexadecazapentacyclo[34.20.11.160,64.041,45.047,51]octahexaconta-60(68),61,63-trien-54-yl]acetic acid	1856135: Inhibition of FITC-labeled Tcf4 (unknown origin) / full length beta-catenin (1 to 781 residues) (unknown origin) protein-protein interaction measured after 1 hr by fluorescence polarization assay	ic50	4.8000	uM
3-[2-(1-hydroxyindazol-5-yl)ethyl]-2H-1,2,4-oxadiazole-5-thione	1979691: Inhibition of wild type beta-Catenin (142 to 686 residues) (unknown origin)/C-terminal fluorescein-labeled human TCF4 (7 to 51 residues) protein-protein interaction assessed as inhibition constant incubated for 30 mins by fluorescence polarization assay	ki	7.2400	uM
7,19-dihydroxy-5,21-bis(2-hydroxypropyl)-6,20-dimethoxy-12,14-dioxahexacyclo[13.8.0.02,11.03,8.04,22.018,23]tricosa-1,3(8),4,6,10,15,18(23),19,21-nonaene-9,17-dione	1288068: Inhibition of human GST tagged Tcf4/beta catenin interaction after 2 hrs using fluorescent AP Attophos substrate by ELISA analysis	ic50	8.7000	uM
7,19-dihydroxy-5,21-bis[(2S)-2-hydroxypropyl]-6,20-dimethoxy-12,14-dioxahexacyclo[13.8.0.02,11.03,8.04,22.018,23]tricosa-1,3(8),4,6,10,15,18(23),19,21-nonaene-9,17-dione	1979676: Inhibition of human beta-Catenin/GST-tagged TCF4 (unknown origin) protein-protein interaction incubated for 2 hrs by ELISA assay	ic50	8.7000	uM
(1R,3R)-9-methoxy-1,3-dimethyl-3,4-dihydro-1H-benzo[g]isochromene-5,10-dione	1979673: Inhibition of beta-Catenin/TCF4 protein-protein interaction in human HEK 293 STF cells	ic50	9.5000	uM
[(2S)-1-[12-[(2S)-2-(2,4-dihydroxy-6-methylbenzoyl)oxypropyl]-3,10-dihydroxy-2,6,7,11-tetramethoxy-4,9-dioxoperylen-1-yl]propan-2-yl] 2,4-dihydroxy-6-methylbenzoate	1850525: Inhibition of beta catenin/recombinant GST tagged Tcf4 protein protein interaction in human HCT-116 cells	ic50	10.0000	uM
[(2S)-1-[3,10-dihydroxy-12-[(2S)-2-(4-hydroxyphenoxy)carbonyloxypropyl]-2,6,7,11-tetramethoxy-4,9-dioxoperylen-1-yl]propan-2-yl] benzoate	1850525: Inhibition of beta catenin/recombinant GST tagged Tcf4 protein protein interaction in human HCT-116 cells	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, increases expression, affects methylation, decreases expression, affects cotreatment (+2 more)	7
Valproic Acid	decreases methylation, decreases expression	5
trichostatin A	decreases reaction, increases reaction, affects cotreatment, decreases expression, affects binding	3
PKF115-584	affects binding, decreases reaction, increases expression	3
Arsenic	decreases expression, increases abundance, affects binding, increases reaction, affects cotreatment	3
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	3
Cisplatin	affects expression, affects cotreatment, decreases expression	3
nickel sulfate	decreases expression, increases expression	2
destruxin B	decreases activity, affects localization, decreases expression, affects cotreatment	2
nitroaspirin	affects reaction, affects expression, affects binding	2
deguelin	decreases expression, increases expression	2
NCX 4040	decreases activity, decreases expression, affects binding, decreases reaction	2
bisphenol S	increases expression, increases methylation	2
Air Pollutants	decreases expression, affects cotreatment, affects expression, increases abundance	2
Aspirin	decreases activity, increases reaction, increases response to substance	2
Estradiol	decreases expression, affects cotreatment, increases expression	2
Sulindac	increases response to substance, decreases activity, increases reaction	2
Tobacco Smoke Pollution	affects binding, decreases reaction, increases activity, decreases expression	2
Tretinoin	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases methylation	1
testosterone enanthate	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, affects expression, increases abundance	1
bisphenol A	affects cotreatment, decreases methylation	1
geraniol	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	decreases methylation	1

ChEMBL screening assays

31 unique, capped per target: 31 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3782566	Binding	Inhibition of His6 tagged Tcf4 1-53/beta catenin (unknown origin) interaction by VP-ITC titration calorimeter method	Target β-catenin/CD44/Nanog axis in colon cancer cells by certain N’-(2-oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazides. — Bioorg Med Chem Lett

Cellosaurus cell lines

30 cell lines: 13 transformed cell line, 7 induced pluripotent stem cell, 6 finite cell line, 3 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A2QA	GM27186	Finite cell line	Female
CVCL_A2QB	GM27239	Transformed cell line	Female
CVCL_A2QL	GM27573	Transformed cell line	Male
CVCL_A2QM	GM27574	Transformed cell line	Male
CVCL_A2VA	GM26023	Finite cell line	Male
CVCL_A4WM	LIBDi011-A	Induced pluripotent stem cell	Female
CVCL_A4WN	LIBDi012-A	Induced pluripotent stem cell	Male
CVCL_A4WQ	LIBDi014-A	Induced pluripotent stem cell	Female
CVCL_A4WS	LIBDi016-A	Induced pluripotent stem cell	Female
CVCL_A4WV	LIBDi019-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)