BCL9

Summary

BCL9 (BCL9 transcription coactivator, HGNC:1008) is a protein-coding gene on chromosome 1q21.2, encoding B-cell CLL/lymphoma 9 protein (O00512). Involved in signal transduction through the Wnt pathway. It is a selective cancer dependency (DepMap: 12.1% of cell lines).

BCL9 is associated with B-cell acute lymphoblastic leukemia. It may be a target of translocation in B-cell malignancies with abnormalities of 1q21. Its function is unknown. The overexpression of BCL9 may be of pathogenic significance in B-cell malignancies.

Source: NCBI Gene 607 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Limited, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 263 total — 4 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 3 cancer types
• Cancer dependency (DepMap): dependent in 12.1% of screened cell lines
• MANE Select transcript: NM_004326

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1008
Approved symbol	BCL9
Name	BCL9 transcription coactivator
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000116128
Ensembl biotype	protein_coding
OMIM	602597
Entrez	607

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000234739, ENST00000497938, ENST00000683836, ENST00000684121

RefSeq mRNA: 1 — MANE Select: NM_004326 NM_004326

CCDS: CCDS30833

Canonical transcript exons

ENST00000234739 — 10 exons

Exon	Start	End
ENSE00000787543	147618816	147621057
ENSE00000824226	147612883	147613199
ENSE00000903093	147622271	147622531
ENSE00001156122	147623842	147626216
ENSE00001156130	147611578	147611889
ENSE00001344643	147606784	147606866
ENSE00001344647	147604777	147604911
ENSE00001344656	147541501	147541674
ENSE00003673699	147615803	147615902
ENSE00003684403	147614427	147614616

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 93.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.7099 / max 328.5775, expressed in 1659 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4979	6.1574	1159
4982	3.7922	1516
4983	1.1200	646
4980	0.3682	181
4981	0.2722	129

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	93.24	gold quality
ganglionic eminence	UBERON:0004023	91.10	gold quality
ventricular zone	UBERON:0003053	90.83	gold quality
islet of Langerhans	UBERON:0000006	86.11	gold quality
right uterine tube	UBERON:0001302	85.17	gold quality
smooth muscle tissue	UBERON:0001135	84.85	gold quality
left uterine tube	UBERON:0001303	84.15	gold quality
body of uterus	UBERON:0009853	84.04	gold quality
lower esophagus muscularis layer	UBERON:0035833	83.17	gold quality
lower esophagus	UBERON:0013473	83.13	gold quality
embryo	UBERON:0000922	82.88	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	82.06	gold quality
vena cava	UBERON:0004087	81.55	gold quality
fallopian tube	UBERON:0003889	81.40	gold quality
cerebellar cortex	UBERON:0002129	81.30	gold quality
cerebellar hemisphere	UBERON:0002245	81.29	gold quality
cardia of stomach	UBERON:0001162	81.14	silver quality
right hemisphere of cerebellum	UBERON:0014890	80.98	gold quality
popliteal artery	UBERON:0002250	80.93	gold quality
tibial artery	UBERON:0007610	80.90	gold quality
endocervix	UBERON:0000458	80.64	gold quality
ventral tegmental area	UBERON:0002691	80.63	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.62	gold quality
muscle layer of sigmoid colon	UBERON:0035805	80.58	gold quality
rectum	UBERON:0001052	80.43	gold quality
right ovary	UBERON:0002118	80.37	gold quality
cerebellum	UBERON:0002037	80.23	gold quality
aorta	UBERON:0000947	80.21	gold quality
mucosa of stomach	UBERON:0001199	80.19	gold quality
saphenous vein	UBERON:0007318	80.15	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.89

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, ESR2, PAX6

miRNA regulators (miRDB)

189 targeting BCL9, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-6825-5P	99.96	69.81	3431

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• crystallographic analysis of how beta-catenin, BCL9, BCL9-2 and Tcf4 interact (PMID:17052462)
• BCL9 itself contains a transcriptional activation domain in the C terminus, which functionally synergizes in lymphoid cells with the C-terminal transactivation domain of beta-catenin. (PMID:18347063)
• Data show that human and Drosophila Pygo PHD fingers associate with their cognate HD1 domains from BCL9/Legless to bind specifically to the histone H3 tail methylated at lysine 4 (H3K4me). (PMID:18498752)
• Overexpression and altered subcellular localization of ATG16L1 protein in human oral squamous-cell carcinoma: correlation with lymphovascular invasion and lymph-node metastasis are reported. (PMID:18789482)
• The amino-terminus of the BCL9 peptide is critical for maintaining the wild-type binding affinity of the BCL9 peptide to beta-catenin. (PMID:19715304)
• Findings suggest that deregulation of BCL9 is an important contributing factor to tumor progression in multiple myeloma and colon neoplasms. (PMID:19738061)
• Pygo2 PHD is the only known PHD finger that is capable of interacting simultaneously with two functional ligands, B9L and BCL9 (PMID:20637214)
• These findings indicate that common variations in the BCL9 gene confer risk of schizophrenia and may also be associated with bipolar disorder and major depressive disorder in the Chinese Han population. (PMID:21383261)
• growth factor induced proliferation mediates a neutralizing response by significantly increasing miR-30c-2* which reduces BCL9 expression and cell proliferation in SKOV-3 and OVCAR-3 cells (PMID:22024689)
• Inhibition of the BCL9-beta-catenin interaction and selectively suppresses oncogenic Wnt transcription. (PMID:22914623)
• we detected five SNPs in the first two genes/loci - BCL9 and C9orf5 - strongly associated with negative symptoms of schizophrenia (PMID:23382809)
• By beta-catenin’s association with LEF1 and BCL9-2/B9L. (PMID:24419084)
• MiR-30-5p downregulation occurs as a result of interaction between multiple myeloma cells and bone marrow stromal cells, which in turn enhances expression of BCL9. (PMID:24599134)
• PCDH10 antagonized MM cell proliferation via the downregulation of Wnt/beta-catenin/BCL-9 signaling, whereas PCDH10 repressed the expression of AKT to promote the expression of GSK3beta and then to restrain the activation of beta-catenin (PMID:26081897)
• BCL9 is a molecular driver of DCIS invasive progression. (PMID:26384318)
• findings indicate that BCL9 most likely does not harbor a common genetic variant that can increase the risk for schizophrenia in the Japanese population (PMID:26494551)
• BCL9/9L-beta-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer (PMID:26844272)
• results from this study demonstrated that hypoxia induced BCL-9 expression in human CRC cells mainly through HIF-1alpha, which could be an important underlying mechanism for increased BCL-9 expression in CRC. (PMID:27121066)
• it was demonstrated that miR218 modulated a novel molecular target and the present study provided novel insights into potential mechanisms of RCC oncogenesis. (PMID:27314976)
• MEF2D-BCL9-positive patients had B-cell precursor immunophenotype and were characterized as being older in age, being resistant to chemotherapy, having very early relapse, and having leukemic blasts that mimic morphologically mature B-cell leukemia with markedly high expression of HDAC9. (PMID:27507882)
• Specific regulation of BCL9 expression by HIF-1alpha may prove to be an underlying crosstalk between Wnt/beta-catenin signaling and hypoxia signaling pathways. (PMID:28074862)
• The authors used CRISPR/Cas9 genome engineering of Drosophila legless (lgs) and human BCL9 and B9L to show that the C-terminus downstream of their adaptor elements is crucial for Wnt responses. (PMID:28296634)
• miR-30a acts as a tumor suppressor by double-targeting COX-2 and BCL9, and significantly affects the development of H. pylori-induced gastric cancer, shedding new light on the mechanisms underlying H. pylori-associated gastric cancer. (PMID:28769030)
• SOX7 inhibits oncogenic beta-catenin-mediated transcription by disrupting the beta-catenin/BCL9 interaction. (PMID:29271667)
• The gene BCL9 is overexpressed in malignant adrenocortical tumors and promotes clonal ACC cell growth. These findings suggest that BCL9 overexpression may serve as an alternative driver of constitutive Wnt/beta-Catenin activation in ACC and could represent a potential molecular and diagnostic marker of tumor malignancy. (PMID:29428231)
• High BCL9 expression is associated with cisplatin-resistance in non-small cell lung cancer. (PMID:30009824)
• Results find that BCL9 is upregulated in osteosarcoma (OS) tissues and promotes OS proliferation, migration and invasion. BCL9 is a downstream target of miR-1301 in OS cells. In addition, BCL9 restoration could reversed the functional effects of miR-1301 overexpression on OS cell proliferation, migration and invasion. These results revealed the important role of BCL9 in OS tumor progression. (PMID:30172867)
• results revealed a novel role of BCL9 in controlling mitotic Wnt signalling to promote cell division and growth. (PMID:30217955)
• We found that miR-532 was significantly upregulated in patients with intervertebral disc degeneration and plays a pro-apoptotic role in human intervertebral disc nucleus pulposus cells. Further, Bcl-9 was confirmed to be a direct target of miR-532 and might be a potential target for disc degeneration therapy. (PMID:30472057)
• SNHG16 promotes BCL9 expression by sponging miR-1301 to facilitate the proliferation, migration and invasion of OS cells. (PMID:30909141)
• MiR-30c exerts tumor suppressive functions in colorectal carcinoma by directly targeting BCL9. (PMID:31081087)
• Investigated targeting the protein interactions of catenin beta 1 and B-cell lymphoma 9 protein (BCL9) binding using peptides designed by peptidomimetic drug design. (PMID:31088961)
• In response to spontaneous calcium transients or cellular stress, BCL9 is recruited adjacent to the interchromosomal regions, where it stabilizes the mRNA of calcium signaling and neural associated genes by interacting with paraspeckle proteins. (PMID:31911584)
• BCL9/BCL9L promotes tumorigenicity through immune-dependent and independent mechanisms in triple negative breast cancer. (PMID:33767438)
• miR-140-3p inhibits colorectal cancer progression and its liver metastasis by targeting BCL9 and BCL2. (PMID:33838016)
• Evidence for frequent concurrent DCUN1D1, FGFR1, BCL9 gene copy number amplification in squamous cell lung cancer. (PMID:33862557)
• LncRNA NCK1-AS1 exerts oncogenic property in gastric cancer by targeting the miR-22-3p/BCL9 axis to activate the Wnt/beta-catenin signaling. (PMID:33974352)
• The interactions of Bcl9/Bcl9L with beta-catenin and Pygopus promote breast cancer growth, invasion, and metastasis. (PMID:34545187)
• Hypoxia-inducible factor 1alpha induces osteo/odontoblast differentiation of human dental pulp stem cells via Wnt/beta-catenin transcriptional cofactor BCL9. (PMID:35027586)
• Prognostic and survival impact of BCL9 and RPS6KB1 copy number variation detected from circulating free DNA in hepatocellular carcinoma. (PMID:36803362)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	bcl9	ENSDARG00000036687
mus_musculus	Bcl9	ENSMUSG00000038256
rattus_norvegicus	Bcl9	ENSRNOG00000017516

Paralogs (1): BCL9L (ENSG00000186174)

Protein

Protein identifiers

B-cell CLL/lymphoma 9 protein — O00512 (reviewed: O00512)

Alternative names: Protein legless homolog

All UniProt accessions (3): O00512, A0A804HI55, A0A804HIV1

UniProt curated annotations — full annotation on UniProt →

Function. Involved in signal transduction through the Wnt pathway. Promotes beta-catenin’s transcriptional activity.

Subunit / interactions. Binds to beta-catenin (CTNNB1), PYGO1 and PYGO2; the interaction with PYGO1 increases PYGO1 affinity to histone H3 methylated at ‘Lys 4’.

Subcellular location. Nucleus.

Tissue specificity. Detected at low levels in thymus, prostate, testis, ovary and small intestine, and at lower levels in spleen, colon and blood.

Disease relevance. A chromosomal aberration involving BCL9 is found in a patient with precursor B-cell acute lymphoblastic leukemia (ALL). Translocation t(1;14)(q21;q32). This translocation leaves the coding region intact, but may have pathogenic effects due to alterations in the expression level of BCL9. Several cases of translocations within the 3’-UTR of BCL9 have been found in B-cell malignancies.

Similarity. Belongs to the BCL9 family.

RefSeq proteins (1): NP_004317* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR015668	Bcl-9/Bcl-9l	Family
IPR024670	BCL9_beta-catenin-bd_dom	Domain

Pfam: PF11502

UniProt features (53 total): compositionally biased region 17, modified residue 12, region of interest 10, mutagenesis site 4, sequence conflict 3, sequence variant 2, strand 2, helix 2, chain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
2VPB	X-RAY DIFFRACTION	1.59
2VPG	X-RAY DIFFRACTION	1.6
2VP7	X-RAY DIFFRACTION	1.65
2VPE	X-RAY DIFFRACTION	1.7
3SL9	X-RAY DIFFRACTION	2.2
2GL7	X-RAY DIFFRACTION	2.6
8Y0P	X-RAY DIFFRACTION	2.62
2VPD	X-RAY DIFFRACTION	2.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00512-F1	43.07	0.03

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 (12): 104, 157, 172, 315, 318, 352, 687, 689, 801, 844, 907, 917

Mutagenesis-validated functional residues (4):

Position	Phenotype
358	abolishes interaction with ctnnb1.
359	abolishes interaction with ctnnb1.
366	abolishes interaction with ctnnb1; when associated with a-369.
369	abolishes interaction with ctnnb1; when associated with a-366.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT

MSigDB gene sets: 304 (showing top): RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, FREAC2_01, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GGTGTGT_MIR329, GOBP_SKELETAL_MUSCLE_TISSUE_REGENERATION, TGCGCANK_UNKNOWN, RORA1_01, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, MAZ_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_GROWTH

GO Biological Process (9): transcription by RNA polymerase II (GO:0006366), myotube differentiation involved in skeletal muscle regeneration (GO:0014908), somatic stem cell population maintenance (GO:0035019), skeletal muscle cell differentiation (GO:0035914), myoblast differentiation (GO:0045445), positive regulation of transcription by RNA polymerase II (GO:0045944), canonical Wnt signaling pathway (GO:0060070), Wnt signaling pathway (GO:0016055), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (3): transcription coactivator activity (GO:0003713), beta-catenin binding (GO:0008013), protein binding (GO:0005515)

GO Cellular Component (7): nucleoplasm (GO:0005654), cis-Golgi network (GO:0005801), sarcoplasm (GO:0016528), beta-catenin-TCF complex (GO:1990907), nucleus (GO:0005634), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	2
Signal Transduction	1
Signaling by WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
DNA-templated transcription	2
cell differentiation	2
positive regulation of DNA-templated transcription	2
cellular anatomical structure	2
cytoplasm	2
myotube differentiation	1
skeletal muscle tissue regeneration	1
stem cell population maintenance	1
skeletal muscle tissue development	1
muscle structure development	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
Wnt signaling pathway	1
cell surface receptor signaling pathway	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
protein binding	1
binding	1
nuclear lumen	1
Golgi apparatus	1
RNA polymerase II transcription regulator complex	1
intracellular anatomical structure	1
endomembrane system	1

Protein interactions and networks

STRING

774 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BCL9	CTNNB1	P35222	996
BCL9	PYGO1	Q9Y3Y4	984
BCL9	PYGO2	Q9BRQ0	981
BCL9	HNF4A	P41235	979
BCL9	LEF1	Q9UJU2	810
BCL9	FCRL5	Q96RD9	721
BCL9	FCRL4	Q96PJ5	709
BCL9	CDC73	Q6P1J9	704
BCL9	AXIN1	O15169	669
BCL9	MYC	P01106	649
BCL9	TCF7L1	Q9HCS4	589
BCL9	BTRC	Q9Y297	588
BCL9	ACP6	Q9NPH0	575
BCL9	BCL9L	Q86UU0	556
BCL9	TERT	O14746	540

IntAct

75 interactions, top by confidence:

A	B	Type	Score
BCL9	CTNNB1	psi-mi:“MI:0915”(physical association)	0.720
CTNNB1	BCL9	psi-mi:“MI:0915”(physical association)	0.720
CTNNB1	BCL9	psi-mi:“MI:0407”(direct interaction)	0.720
PYGO1	BCL9	psi-mi:“MI:0914”(association)	0.700
PYGO1	BCL9	psi-mi:“MI:0407”(direct interaction)	0.700
BCL9	PYGO1	psi-mi:“MI:0407”(direct interaction)	0.700
BCL9	PYGO1	psi-mi:“MI:0915”(physical association)	0.700
PYGO1	BCL9	psi-mi:“MI:0915”(physical association)	0.700
BCL9	PYGO2	psi-mi:“MI:0915”(physical association)	0.690
PYGO2	BCL9	psi-mi:“MI:0914”(association)	0.690
PYGO2	BCL9	psi-mi:“MI:0915”(physical association)	0.690
CDC73	BCL9	psi-mi:“MI:0915”(physical association)	0.560
CDC73	BCL9	psi-mi:“MI:0914”(association)	0.560
arm	BCL9	psi-mi:“MI:0915”(physical association)	0.550
BCL9	arm	psi-mi:“MI:0915”(physical association)	0.550
FOS	MYO1C	psi-mi:“MI:2364”(proximity)	0.480
MAP1LC3A	BCL9	psi-mi:“MI:0407”(direct interaction)	0.440
BCL9		psi-mi:“MI:0407”(direct interaction)	0.440
TCF4	BCL9	psi-mi:“MI:0915”(physical association)	0.400
Ctnnb1	BCL9	psi-mi:“MI:0915”(physical association)	0.370
BCL9	pygo	psi-mi:“MI:0915”(physical association)	0.370
pygo	BCL9	psi-mi:“MI:0915”(physical association)	0.370
CTNNA1	BCL9	psi-mi:“MI:0914”(association)	0.350

BioGRID (114): CTNNB1 (Affinity Capture-Western), BCL9 (Proximity Label-MS), BCL9 (Affinity Capture-MS), BCL9 (Reconstituted Complex), BCL9 (Proximity Label-MS), BCL9 (Affinity Capture-RNA), HSPA8 (Affinity Capture-MS), HSPA1B (Affinity Capture-MS), KIF11 (Affinity Capture-MS), PYGO2 (Affinity Capture-MS), CTNNB1 (Affinity Capture-MS), USP9X (Affinity Capture-MS), PYGO1 (Affinity Capture-MS), PLEC (Affinity Capture-MS), EPPK1 (Affinity Capture-MS)

ESM2 similar proteins: A1YFU7, A2AJK6, A2BH40, B2RWS6, D3YWE6, E9Q4N7, M9NEY8, O00512, O14497, O35126, O42368, O43365, O57401, P02831, P02833, P22810, P23441, P23512, P25822, P32182, P34545, P35582, P35583, P43698, P43699, P50220, P50901, P54258, P54259, P54269, P55317, Q06A37, Q08DG7, Q08E31, Q09472, Q0VCT9, Q10571, Q1KKX7, Q24248, Q24645

Diamond homologs: O00512, Q67FY2, Q67FY3, Q86UU0, Q95KQ6, Q9D219

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
BCL9	up-regulates	CTNNB1	binding
BCL9	up-regulates	PYGO1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 64 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of the nephric duct	5	73.8×	7e-07
Deactivation of the beta-catenin transactivating complex	7	37.9×	1e-07
Gastrulation	5	30.2×	3e-05
TCF dependent signaling in response to WNT	6	16.4×	7e-05
Formation of the beta-catenin:TCF transactivating complex	5	14.0×	7e-04
Signaling by WNT	5	13.0×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
neuron fate specification	6	72.6×	3e-08
branching involved in ureteric bud morphogenesis	5	31.6×	3e-05
neuroblast proliferation	5	31.6×	3e-05
positive regulation of miRNA transcription	6	30.1×	4e-06
inner ear morphogenesis	5	25.9×	6e-05
retina development in camera-type eye	5	22.0×	1e-04
anatomical structure morphogenesis	9	21.6×	4e-08
somatic stem cell population maintenance	5	21.4×	1e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 3 cancer types — COAD, COADREAD, STAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	228
Likely benign	10
Benign	3

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1703635	GRCh37/hg19 1q21.1-21.2(chr1:146043713-147830830)	Pathogenic
2498453	GRCh37/hg19 1q21.1-21.2(chr1:146405854-147597284)x1	Pathogenic
2506525	GRCh37/hg19 1q21.1-21.2(chr1:146465878-147416212)	Pathogenic
980944	GRCh37/hg19 1q21.1-21.2(chr1:146112080-147819815)x3	Pathogenic

SpliceAI

2080 predictions. Top by Δscore:

Variant	Effect	Δscore
1:147614425:A:AG	acceptor_gain	1.0000
1:147614426:G:GG	acceptor_gain	1.0000
1:147614426:GAAT:G	acceptor_gain	1.0000
1:147614582:GTGGT:G	donor_gain	1.0000
1:147614609:GCCAA:G	donor_gain	1.0000
1:147614613:A:AG	donor_gain	1.0000
1:147614617:G:GG	donor_gain	1.0000
1:147615801:A:AG	acceptor_gain	1.0000
1:147615802:G:GG	acceptor_gain	1.0000
1:147618815:GAAC:G	acceptor_gain	1.0000
1:147604908:AAAG:A	donor_loss	0.9900
1:147604909:AAGGT:A	donor_loss	0.9900
1:147604910:AG:A	donor_loss	0.9900
1:147604911:GG:G	donor_loss	0.9900
1:147604912:G:GA	donor_loss	0.9900
1:147604913:T:A	donor_loss	0.9900
1:147614422:TTTA:T	acceptor_loss	0.9900
1:147614424:TA:T	acceptor_loss	0.9900
1:147614425:AGAAT:A	acceptor_gain	0.9900
1:147614426:GA:G	acceptor_gain	0.9900
1:147614426:GAATG:G	acceptor_gain	0.9900
1:147614612:AATAA:A	donor_gain	0.9900
1:147614614:TAA:T	donor_gain	0.9900
1:147614614:TAAGT:T	donor_loss	0.9900
1:147614615:AAGTA:A	donor_loss	0.9900
1:147614616:AG:A	donor_loss	0.9900
1:147614618:T:A	donor_loss	0.9900
1:147614619:A:AG	donor_loss	0.9900
1:147615800:CAG:C	acceptor_gain	0.9900
1:147615801:AGA:A	acceptor_gain	0.9900

AlphaMissense

9384 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:147614595:T:C	F180S	1.000
1:147614609:G:C	A185P	1.000
1:147614610:C:A	A185D	1.000
1:147615804:G:C	A188P	1.000
1:147615805:C:A	A188D	1.000
1:147615807:G:C	A189P	1.000
1:147615817:T:A	V192D	1.000
1:147619222:T:C	L356P	1.000
1:147619228:A:C	H358P	1.000
1:147619231:G:C	R359P	1.000
1:147619237:G:C	R361P	1.000
1:147619239:T:C	S362P	1.000
1:147619240:C:T	S362F	1.000
1:147619243:T:C	L363S	1.000
1:147619246:A:C	Q364P	1.000
1:147619252:T:A	L366H	1.000
1:147619252:T:C	L366P	1.000
1:147619258:A:C	D368A	1.000
1:147619258:A:G	D368G	1.000
1:147619258:A:T	D368V	1.000
1:147619261:T:A	I369N	1.000
1:147619261:T:C	I369T	1.000
1:147619261:T:G	I369S	1.000
1:147619264:A:C	Q370P	1.000
1:147619267:G:C	R371P	1.000
1:147619273:T:C	L373P	1.000
1:147619569:T:A	W472R	1.000
1:147619569:T:C	W472R	1.000
1:147619570:G:C	W472S	1.000
1:147619571:G:C	W472C	1.000

dbSNP variants (sampled 300 via entrez): RS1000044846 (1:147543826 C>T), RS1000113498 (1:147580975 C>T), RS1000230405 (1:147625937 C>T), RS1000239110 (1:147606267 A>G,T), RS1000257891 (1:147562166 T>C), RS1000365030 (1:147568015 G>A), RS1000453961 (1:147612757 G>A), RS1000606170 (1:147593361 C>T), RS1000666453 (1:147555216 A>G), RS1000698638 (1:147600293 C>A,T), RS1000779020 (1:147554939 C>G), RS1000805569 (1:147574323 G>A), RS1000847825 (1:147580014 A>G,T), RS1001050889 (1:147542194 G>A), RS1001218608 (1:147587418 T>C)

Disease associations

OMIM: gene MIM:602597 | disease phenotypes: MIM:612475, MIM:192500

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Limited	AD

Mondo (3): chromosome 1q21.1 duplication syndrome (MONDO:0012915), familial long QT syndrome (MONDO:0019171), congenital heart disease (MONDO:0005453)

Orphanet (3): 1q21.1 microduplication syndrome (Orphanet:250994), Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768)

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001836_2	Schizophrenia (negative symptoms)	6.000000e-07
GCST002178_8	Adverse response to chemotherapy in breast cancer (alopecia) (cyclophosphamide+doxorubicin+/-5FU)	6.000000e-07
GCST002806_16	Type 2 diabetes	6.000000e-06
GCST004766_1	Triglyceride change in response to fenofibrate in statin-treated type 2 diabetes	3.000000e-08
GCST010988_253	Adult body size	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007681	triglyceride change measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
C567290	Chromosome 1q21.1 Duplication Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3712821 (SINGLE PROTEIN), CHEMBL3885525 (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: 74,559 (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
CHEMBL50	QUERCETIN	3	74,559

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

Binding affinities (BindingDB)

6 measured of 6 human assays (6 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-(3-((S)-3-Ethyl-4-(4’-fluoro-6- (((S)-pyrrolidin-1-ium-3-yl)oxy)- [1,1’-biphenyl]-3-carbonyl) piperazine-1-carbonyl)-5- fluorophenyl)piperazin-1-ium chloride	KI	10000 nM	US-11634409: Compounds for the treatment of BRAF-associated diseases and disorders
(S)-1-(3-Fluoro-5-(4-(4-(pyrrolidin- 3-yloxy)-3-(4-(trifluoromethyl) cyclohexyl)benzoyl)piperazine-1- carbonyl)phenyl)piperazin-2-one hydrochloride	KI	14000 nM	US-11634409: Compounds for the treatment of BRAF-associated diseases and disorders
4-(3-Fluoro-5-((5)-4-(4’-fluoro-6- (((S)-pyrrolidin-1-ium-3-yl)oxy)- [1,1’-biphenyl]-3-carbonyl)-3- isobutylpiperazine-1-carbonyl) phenyl)piperazin-1-ium chloride	KI	22000 nM	US-11634409: Compounds for the treatment of BRAF-associated diseases and disorders
(S)-1-(3-(4-(3-Cyclohexyl-4- (pyrrolidin-3-yloxy)benzoyl) piperazine-1-carbonyl)-5- fluorophenyl)piperazin-2-one hydrochloride	KI	39000 nM	US-11634409: Compounds for the treatment of BRAF-associated diseases and disorders
4-(3-Fluoro-5-((5)-4-(4’-fluoro-6- (((S)-pyrrolidin-1-ium-3-yl)oxy)- [1,1’-biphenyl]-3-carbonyl)-3- isopropylpiperazine-1-carbonyl) phenyl)piperazin-1-ium chloride	KI	45000 nM	US-11634409: Compounds for the treatment of BRAF-associated diseases and disorders
4-(3-Fluoro-5-((S)-4-(4’-fluoro-6- (((S)-pyrrolidin-1-ium-3-yl)oxy)-[1,1’- biphenyl]-3-carbonyl)-3- methylpiperazine-1-carbonyl) phenyl)piperazin-1-ium chloride	KI	110000 nM	US-11634409: Compounds for the treatment of BRAF-associated diseases and disorders

ChEMBL bioactivities

282 potent at pChembl≥5 of 495 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.33	Ki	470	nM	CHEMBL4762534
6.33	Ki	470	nM	CHEMBL4462309
6.19	IC50	650	nM	CHEMBL5398967
6.16	IC50	690	nM	CHEMBL5398967
6.14	IC50	720	nM	CHEMBL5416539
6.12	Ki	760	nM	CHEMBL4846565
6.11	Kd	770	nM	CHEMBL4871137
6.09	IC50	820	nM	CHEMBL5416539
6.07	Ki	850	nM	CHEMBL5190873
6.06	IC50	870	nM	CHEMBL4846565
6.05	IC50	890	nM	CHEMBL5404409
6.04	IC50	910	nM	CHEMBL5413417
6.03	IC50	940	nM	CHEMBL5413417
6.02	IC50	960	nM	CHEMBL5190873
6.02	Ki	960	nM	CHEMBL5280053
6.00	Ki	1000	nM	CHEMBL4462309
6.00	IC50	1000	nM	CHEMBL5422967
5.96	IC50	1100	nM	CHEMBL5399058
5.96	IC50	1100	nM	CHEMBL5440529
5.95	IC50	1130	nM	CHEMBL5398170
5.93	IC50	1180	nM	CHEMBL5440529
5.93	IC50	1180	nM	CHEMBL5400908
5.93	IC50	1180	nM	CHEMBL5574223
5.92	IC50	1200	nM	CHEMBL4583576
5.92	IC50	1200	nM	CHEMBL4846565
5.92	Ki	1200	nM	CHEMBL5208427
5.92	IC50	1200	nM	CHEMBL5280053
5.92	Ki	1200	nM	CHEMBL5280053
5.92	IC50	1190	nM	CHEMBL5422967
5.90	IC50	1270	nM	CHEMBL5398170
5.89	Ki	1300	nM	CHEMBL4549859
5.89	Ki	1300	nM	CHEMBL4583576
5.88	IC50	1310	nM	CHEMBL5418296
5.88	IC50	1330	nM	CHEMBL5397851
5.87	IC50	1360	nM	CHEMBL5400908
5.87	IC50	1350	nM	CHEMBL5570851
5.86	IC50	1380	nM	CHEMBL5399058
5.85	IC50	1400	nM	CHEMBL5208427
5.85	IC50	1420	nM	CHEMBL5573872
5.83	IC50	1490	nM	CHEMBL5420343
5.82	Ki	1500	nM	CHEMBL4074243
5.82	IC50	1500	nM	CHEMBL5280053
5.80	Kd	1590	nM	CHEMBL4074243
5.80	Ki	1600	nM	CHEMBL4783692
5.80	IC50	1580	nM	CHEMBL5406240
5.79	IC50	1640	nM	CHEMBL5571557
5.79	IC50	1610	nM	CHEMBL5570927
5.78	IC50	1650	nM	CHEMBL5572538
5.75	Ki	1800	nM	CHEMBL5187855
5.74	IC50	1830	nM	CHEMBL5573731

PubChem BioAssay actives

256 with measured affinity, of 588 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-(3,4-difluorophenyl)-4-[(3S)-pyrrolidin-3-yl]oxy-N-[4-[(3S)-pyrrolidin-3-yl]oxy-3-[3-(2H-tetrazol-5-yl)phenyl]phenyl]benzamide;dihydrochloride	1966236: Inhibition of beta-catenin (unknown origin)/BCL9 (unknown origin) protein-protein interaction assessed as inhibition constant by AlphaScreen assay	ki	0.4700	uM
3-(3,4-difluorophenyl)-4-[(3S)-pyrrolidin-3-yl]oxy-N-[4-[(3R)-pyrrolidin-3-yl]oxy-3-[3-(2H-tetrazol-5-yl)phenyl]phenyl]benzamide;dihydrochloride	1686801: Inhibition of protein interaction between C-terminal 6x-histidine tagged full-length beta-catenin (1 to 781 residues) (unknown origin)/N-terminal biotinylated human BCL9 ( 350 to 375 residues) incubated for 1 hr by Alpha-screen competitive inhibition assay	ki	0.4700	uM
2-methyl-2-[3-[(3R)-1-[3-(4-propan-2-ylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]-N-[4-(trifluoromethyl)phenyl]sulfonylpropanamide	1966238: Inhibition of N-terminal His6-tagged full-length recombinant beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 DE3/N-terminal FAM tagged BCL9 HD2(350 to 375 residues) (unknown origin) protein-protein interaction assessed as inhibition constant incubated for 3 hrs by competitive fluorescence polarization assay	ic50	0.6500	uM
2-methyl-2-[3-[1-[3-(4-propan-2-ylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]-N-[4-(trifluoromethyl)phenyl]sulfonylpropanamide	1966238: Inhibition of N-terminal His6-tagged full-length recombinant beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 DE3/N-terminal FAM tagged BCL9 HD2(350 to 375 residues) (unknown origin) protein-protein interaction assessed as inhibition constant incubated for 3 hrs by competitive fluorescence polarization assay	ic50	0.7200	uM
(3R)-N-cyclopropyl-1-[3-(2-methyl-1-oxo-1-piperazin-1-ylpropan-2-yl)oxyphenyl]-N-[[4-(1H-pyrazol-4-yl)phenyl]methyl]piperidine-3-carboxamide;hydrochloride	1781263: Inhibition of C-terminal 6-His-tagged beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3)-N-terminal biotinylated human BCL9 (350 to 375 residues) protein-protein interaction incubated for 1 hr by Alphascreen assay	ki	0.7600	uM
(3R)-N-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethyl]-1-[3-(2-methyl-1-oxo-1-piperazin-1-ylpropan-2-yl)oxyphenyl]-N-[[4-(1H-pyrazol-4-yl)phenyl]methyl]piperidine-3-carboxamide	1781265: Competitive binding affinity to C-terminal 6-His-tagged beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3)- N-terminal biotinylated human BCL9 (350 to 375 residues) assessed as apparent dissociation constant incubated for 2 hrs by AlphaScreen assay	kd	0.7700	uM
(3R)-N-cyclopropyl-1-[3-(2-methyl-1-oxo-1-piperazin-1-ylpropan-2-yl)oxyphenyl]-N-[[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl]methyl]piperidine-3-carboxamide;hydrochloride	1910851: Inhibition of full length beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3)-N-terminal biotinylated human BCL9 (350 to 375 residues) protein-protein interaction incubated for 1 hr by Alphascreen assay	ki	0.8500	uM
N-(4-acetamidophenyl)sulfonyl-2-methyl-2-[3-[1-[3-(4-propan-2-ylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]propanamide	1966238: Inhibition of N-terminal His6-tagged full-length recombinant beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 DE3/N-terminal FAM tagged BCL9 HD2(350 to 375 residues) (unknown origin) protein-protein interaction assessed as inhibition constant incubated for 3 hrs by competitive fluorescence polarization assay	ic50	0.8900	uM
2-methyl-2-[3-[1-[3-(4-propan-2-ylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]-N-thiophen-2-ylsulfonylpropanamide	1966238: Inhibition of N-terminal His6-tagged full-length recombinant beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 DE3/N-terminal FAM tagged BCL9 HD2(350 to 375 residues) (unknown origin) protein-protein interaction assessed as inhibition constant incubated for 3 hrs by competitive fluorescence polarization assay	ic50	0.9100	uM
2-[1-[3-(4-tert-butylcyclohexyl)-4-[(3S)-pyrrolidin-3-yl]oxybenzoyl]piperidin-4-yl]oxy-4-piperazin-1-ylbenzonitrile;dihydrochloride	1925278: Inhibition of full length beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3)/N-terminal biotinylated human BCL9 HD2 (350 to 375 residues) protein-protein interaction assessed as inhibition constant incubated for 1 hr by Alphascreen assay	ki	0.9600	uM
2-methyl-2-[3-[1-[3-(4-propan-2-ylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]-N-[4-(trifluoromethoxy)phenyl]sulfonylpropanamide	1966238: Inhibition of N-terminal His6-tagged full-length recombinant beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 DE3/N-terminal FAM tagged BCL9 HD2(350 to 375 residues) (unknown origin) protein-protein interaction assessed as inhibition constant incubated for 3 hrs by competitive fluorescence polarization assay	ic50	1.0000	uM
2-methyl-2-[3-[(3S)-1-[3-(4-propan-2-ylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]-N-[4-(trifluoromethyl)phenyl]sulfonylpropanamide	1966238: Inhibition of N-terminal His6-tagged full-length recombinant beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 DE3/N-terminal FAM tagged BCL9 HD2(350 to 375 residues) (unknown origin) protein-protein interaction assessed as inhibition constant incubated for 3 hrs by competitive fluorescence polarization assay	ic50	1.1000	uM
N-(benzenesulfonyl)-2-methyl-2-[3-[1-[3-(4-propan-2-ylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]propanamide	1966239: Inhibition of beta-catenin/BCL9 protein-protein interaction in Wnt-dependent human HCT-116 cells assessed as reduction in Axin2 expression level by qRT-PCR assay	ic50	1.1000	uM
N-(3-cyanophenyl)sulfonyl-2-methyl-2-[3-[1-[3-(4-propan-2-ylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]propanamide	1966239: Inhibition of beta-catenin/BCL9 protein-protein interaction in Wnt-dependent human HCT-116 cells assessed as reduction in Axin2 expression level by qRT-PCR assay	ic50	1.1300	uM
N-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-2-methyl-2-[3-[1-[3-(4-propan-2-ylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]propanamide	1966238: Inhibition of N-terminal His6-tagged full-length recombinant beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 DE3/N-terminal FAM tagged BCL9 HD2(350 to 375 residues) (unknown origin) protein-protein interaction assessed as inhibition constant incubated for 3 hrs by competitive fluorescence polarization assay	ic50	1.1800	uM
N-[2-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]-2-[3-[(3R)-3-[[cyclopropyl-[[4-(1H-pyrazol-4-yl)phenyl]methyl]carbamoyl]amino]piperidin-1-yl]phenoxy]-2-methylpropanamide	2109718: Inhibition of full length his-tagged human beta-catenin (1 to 781 residues) expressed in Escherichia coli DE3/N-terminal FAM-tagged human BCL9 (350 to 375 residues) protein-protein interaction incubated for 2 hrs by fluorescence polarization assay	ic50	1.1800	uM
3-(1-benzothiophen-6-yl)-N-[3-(4-fluorophenyl)-4-[(3S)-pyrrolidin-3-yl]oxyphenyl]-4-[(3S)-pyrrolidin-3-yl]oxybenzamide;dihydrochloride	1686813: Inhibition of protein interaction between beta-catenin (unknown origin)/BCL9 in human SW480 cells transfected with beta-catenin assessed as reduction in Wnt/beta-catenin transactivation incubated for 24 hrs by Wnt-responsive TOP-Flash luciferase reporter assay	ic50	1.2000	uM
(3R)-N-cyclopropyl-N-[[4-(1H-indol-3-yl)phenyl]methyl]-1-[3-(2-methyl-1-oxo-1-piperazin-1-ylpropan-2-yl)oxyphenyl]piperidine-3-carboxamide;hydrochloride	1910851: Inhibition of full length beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3)-N-terminal biotinylated human BCL9 (350 to 375 residues) protein-protein interaction incubated for 1 hr by Alphascreen assay	ki	1.2000	uM
3-(6-fluoronaphthalen-2-yl)-N-[3-(4-fluorophenyl)-4-[(3S)-pyrrolidin-3-yl]oxyphenyl]-4-[(3S)-pyrrolidin-3-yl]oxybenzamide;dihydrochloride	1686801: Inhibition of protein interaction between C-terminal 6x-histidine tagged full-length beta-catenin (1 to 781 residues) (unknown origin)/N-terminal biotinylated human BCL9 ( 350 to 375 residues) incubated for 1 hr by Alpha-screen competitive inhibition assay	ki	1.3000	uM
2-[3-[1-[3-(4-tert-butylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]-2-methylpropanoic acid	1966239: Inhibition of beta-catenin/BCL9 protein-protein interaction in Wnt-dependent human HCT-116 cells assessed as reduction in Axin2 expression level by qRT-PCR assay	ic50	1.3100	uM
2-methyl-2-[3-[1-[3-(4-propan-2-ylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]-N-[3-(trifluoromethyl)phenyl]sulfonylpropanamide	1966239: Inhibition of beta-catenin/BCL9 protein-protein interaction in Wnt-dependent human HCT-116 cells assessed as reduction in Axin2 expression level by qRT-PCR assay	ic50	1.3300	uM
methyl 2-[[2-[3-[(3R)-3-[[cyclopropyl-[[4-(1H-pyrazol-4-yl)phenyl]methyl]carbamoyl]amino]piperidin-1-yl]phenoxy]-2-methylpropanoyl]amino]acetate	2109718: Inhibition of full length his-tagged human beta-catenin (1 to 781 residues) expressed in Escherichia coli DE3/N-terminal FAM-tagged human BCL9 (350 to 375 residues) protein-protein interaction incubated for 2 hrs by fluorescence polarization assay	ic50	1.3500	uM
N-[2-[(2S)-2-(aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]-2-[3-[(3S)-3-[[cyclopropyl-[[6-(1H-pyrazol-4-yl)-3-pyridinyl]methyl]carbamoyl]amino]piperidin-1-yl]phenoxy]-2-methylpropanamide	2109718: Inhibition of full length his-tagged human beta-catenin (1 to 781 residues) expressed in Escherichia coli DE3/N-terminal FAM-tagged human BCL9 (350 to 375 residues) protein-protein interaction incubated for 2 hrs by fluorescence polarization assay	ic50	1.4200	uM
N-(4-cyanophenyl)sulfonyl-2-methyl-2-[3-[1-[3-(4-propan-2-ylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]propanamide	1966239: Inhibition of beta-catenin/BCL9 protein-protein interaction in Wnt-dependent human HCT-116 cells assessed as reduction in Axin2 expression level by qRT-PCR assay	ic50	1.4900	uM
3-(3,4-difluorophenyl)-N-[3-(4-fluorophenyl)-4-[(3S)-pyrrolidin-3-yl]oxyphenyl]-4-[(3S)-pyrrolidin-3-yl]oxybenzamide;dihydrochloride	1686801: Inhibition of protein interaction between C-terminal 6x-histidine tagged full-length beta-catenin (1 to 781 residues) (unknown origin)/N-terminal biotinylated human BCL9 ( 350 to 375 residues) incubated for 1 hr by Alpha-screen competitive inhibition assay	ki	1.5000	uM
2-methyl-2-[3-[1-[3-(4-propan-2-ylphenyl)phenyl]sulfonylpiperidin-3-yl]phenoxy]propanoic acid	1966238: Inhibition of N-terminal His6-tagged full-length recombinant beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 DE3/N-terminal FAM tagged BCL9 HD2(350 to 375 residues) (unknown origin) protein-protein interaction assessed as inhibition constant incubated for 3 hrs by competitive fluorescence polarization assay	ic50	1.5800	uM
3-(1-benzothiophen-6-yl)-4-[(3S)-pyrrolidin-3-yl]oxy-N-[4-[(3R)-pyrrolidin-3-yl]oxy-3-[3-(2H-tetrazol-5-yl)phenyl]phenyl]benzamide;dihydrochloride	1686801: Inhibition of protein interaction between C-terminal 6x-histidine tagged full-length beta-catenin (1 to 781 residues) (unknown origin)/N-terminal biotinylated human BCL9 ( 350 to 375 residues) incubated for 1 hr by Alpha-screen competitive inhibition assay	ki	1.6000	uM
2-[3-[(3S)-3-[[cyclopropyl-[[4-(1H-pyrazol-4-yl)phenyl]methyl]carbamoyl]amino]piperidin-1-yl]phenoxy]-N-[2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl]-2-methylpropanamide	2109718: Inhibition of full length his-tagged human beta-catenin (1 to 781 residues) expressed in Escherichia coli DE3/N-terminal FAM-tagged human BCL9 (350 to 375 residues) protein-protein interaction incubated for 2 hrs by fluorescence polarization assay	ic50	1.6100	uM
N-[2-[(2S)-2-(aminomethyl)piperidin-1-yl]-2-oxoethyl]-2-[3-[(3R)-3-[[cyclopropyl-[[4-(1H-pyrazol-4-yl)phenyl]methyl]carbamoyl]amino]piperidin-1-yl]phenoxy]-2-methylpropanamide	2109718: Inhibition of full length his-tagged human beta-catenin (1 to 781 residues) expressed in Escherichia coli DE3/N-terminal FAM-tagged human BCL9 (350 to 375 residues) protein-protein interaction incubated for 2 hrs by fluorescence polarization assay	ic50	1.6400	uM
2-[3-[(3S)-3-[[cyclopropyl-[[4-(1H-pyrazol-4-yl)phenyl]methyl]carbamoyl]amino]piperidin-1-yl]phenoxy]-N-[2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-oxoethyl]-2-methylpropanamide	2109718: Inhibition of full length his-tagged human beta-catenin (1 to 781 residues) expressed in Escherichia coli DE3/N-terminal FAM-tagged human BCL9 (350 to 375 residues) protein-protein interaction incubated for 2 hrs by fluorescence polarization assay	ic50	1.6500	uM
(3R)-N-cyclopropyl-1-[3-(2-methyl-1-oxo-1-piperazin-1-ylpropan-2-yl)oxyphenyl]-N-[[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]methyl]piperidine-3-carboxamide;hydrochloride	1910851: Inhibition of full length beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3)-N-terminal biotinylated human BCL9 (350 to 375 residues) protein-protein interaction incubated for 1 hr by Alphascreen assay	ki	1.8000	uM
2-[3-[(3S)-3-[[cyclopropyl-[[4-(1H-pyrazol-4-yl)phenyl]methyl]carbamoyl]amino]piperidin-1-yl]phenoxy]-N-[2-[(2S)-2-[(dimethylamino)methyl]pyrrolidin-1-yl]-2-oxoethyl]-2-methylpropanamide	2109718: Inhibition of full length his-tagged human beta-catenin (1 to 781 residues) expressed in Escherichia coli DE3/N-terminal FAM-tagged human BCL9 (350 to 375 residues) protein-protein interaction incubated for 2 hrs by fluorescence polarization assay	ic50	1.8200	uM
N-(2-aminoethyl)-2-[3-[(3S)-3-[[cyclopropyl-[[4-(1H-pyrazol-4-yl)phenyl]methyl]carbamoyl]amino]piperidin-1-yl]phenoxy]-2-methylpropanamide	2109718: Inhibition of full length his-tagged human beta-catenin (1 to 781 residues) expressed in Escherichia coli DE3/N-terminal FAM-tagged human BCL9 (350 to 375 residues) protein-protein interaction incubated for 2 hrs by fluorescence polarization assay	ic50	1.8300	uM
(3R)-N-(2-ethoxyethyl)-1-[3-(2-methyl-1-oxo-1-piperazin-1-ylpropan-2-yl)oxyphenyl]-N-[[4-(1H-pyrazol-4-yl)phenyl]methyl]piperidine-3-carboxamide;hydrochloride	1781263: Inhibition of C-terminal 6-His-tagged beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3)-N-terminal biotinylated human BCL9 (350 to 375 residues) protein-protein interaction incubated for 1 hr by Alphascreen assay	ki	1.9000	uM
3-(3,4-difluorophenyl)-N-[3-(4-fluoro-2-methylphenyl)-4-[(3S)-pyrrolidin-3-yl]oxyphenyl]-4-[(3S)-pyrrolidin-3-yl]oxybenzamide;dihydrochloride	1686813: Inhibition of protein interaction between beta-catenin (unknown origin)/BCL9 in human SW480 cells transfected with beta-catenin assessed as reduction in Wnt/beta-catenin transactivation incubated for 24 hrs by Wnt-responsive TOP-Flash luciferase reporter assay	ic50	2.0000	uM
(3R)-N-cyclopropyl-N-[[4-(1H-indazol-4-yl)phenyl]methyl]-1-[3-(2-methyl-1-oxo-1-piperazin-1-ylpropan-2-yl)oxyphenyl]piperidine-3-carboxamide;hydrochloride	1910851: Inhibition of full length beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3)-N-terminal biotinylated human BCL9 (350 to 375 residues) protein-protein interaction incubated for 1 hr by Alphascreen assay	ki	2.0000	uM
N-[2-[2-(2-aminoethyl)pyrrolidin-1-yl]-2-oxoethyl]-2-[3-[(3S)-3-[[cyclopropyl-[[4-(1H-pyrazol-4-yl)phenyl]methyl]carbamoyl]amino]piperidin-1-yl]phenoxy]-2-methylpropanamide	2109718: Inhibition of full length his-tagged human beta-catenin (1 to 781 residues) expressed in Escherichia coli DE3/N-terminal FAM-tagged human BCL9 (350 to 375 residues) protein-protein interaction incubated for 2 hrs by fluorescence polarization assay	ic50	2.0600	uM
3-(3,4-difluorophenyl)-N-[3-(4-fluorophenyl)-4-[(3S)-pyrrolidin-3-yl]oxyphenyl]-4-[(3S)-pyrrolidin-3-yl]oxybenzamide	1979699: Inhibition of His6-tagged human beta-Catenin (138 to 686 residues)/biotinylated human BCL9 (350 to 375 residues) protein-protein interaction assessed as inhibition constant by AlphaScreen competitive assay	ki	2.1000	uM
3-(3,4-difluorophenyl)-N-[3-(4-fluorophenyl)-4-pyrrolidin-3-yloxyphenyl]-4-[(3S)-pyrrolidin-3-yl]oxybenzamide;dihydrochloride	1308849: Competitive inhibition of wild type beta-catenin (unknown origin) expressed in Escherichia coli BL21 DE3 interaction with N-terminally biotinylated human BCL9 (350 to 375 residues) by alpha screen assay	ki	2.1000	uM
3-(3,4-difluorophenyl)-N-[3-(4-fluorophenyl)-4-[(3R)-pyrrolidin-3-yl]oxyphenyl]-4-[(3S)-pyrrolidin-3-yl]oxybenzamide;dihydrochloride	1966235: Inhibition of beta-catenin (unknown origin)/human BCL9 (350 to 375 residues) protein-protein interaction assessed as inhibition constant by AlphaScreen assay	ki	2.1000	uM
(3R)-N-ethyl-1-[3-(2-methyl-1-oxo-1-piperazin-1-ylpropan-2-yl)oxyphenyl]-N-[[4-(1H-pyrazol-4-yl)phenyl]methyl]piperidine-3-carboxamide;hydrochloride	1781263: Inhibition of C-terminal 6-His-tagged beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3)-N-terminal biotinylated human BCL9 (350 to 375 residues) protein-protein interaction incubated for 1 hr by Alphascreen assay	ki	2.1000	uM
(4-nitrophenyl) butanoate	2109717: Inhibition of beta-catenin (unknown origin)/BCL9 (unknown origin) protein-protein interaction	ki	2.1000	uM
6-(3,4-difluorophenyl)-3-[3-(4-fluorophenyl)-4-[(3S)-pyrrolidin-3-yl]oxyphenyl]-7-[(3S)-pyrrolidin-3-yl]oxyquinoline;dihydrochloride	1686801: Inhibition of protein interaction between C-terminal 6x-histidine tagged full-length beta-catenin (1 to 781 residues) (unknown origin)/N-terminal biotinylated human BCL9 ( 350 to 375 residues) incubated for 1 hr by Alpha-screen competitive inhibition assay	ki	2.2000	uM
[3-(4-tert-butylcyclohexyl)-4-[(3S)-pyrrolidin-3-yl]oxyphenyl]-[4-(2-chloro-5-piperazin-1-ylphenoxy)piperidin-1-yl]methanone;dihydrochloride	1925278: Inhibition of full length beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3)/N-terminal biotinylated human BCL9 HD2 (350 to 375 residues) protein-protein interaction assessed as inhibition constant incubated for 1 hr by Alphascreen assay	ki	2.2000	uM
N-[2-[(2S)-2-(aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]-2-[3-[(3R)-3-[[cyclopropyl-[[6-(1H-pyrazol-4-yl)-3-pyridinyl]methyl]carbamoyl]amino]piperidin-1-yl]phenoxy]-2-methylpropanamide	2109718: Inhibition of full length his-tagged human beta-catenin (1 to 781 residues) expressed in Escherichia coli DE3/N-terminal FAM-tagged human BCL9 (350 to 375 residues) protein-protein interaction incubated for 2 hrs by fluorescence polarization assay	ic50	2.2100	uM
2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-8-(4-methylphenyl)chromen-4-one	2005038: Inhibition of full length beta-catenin (unknown origin)/FAM labeled BCL9 (350 to 375 residues) (unknown origin) protein-protein interaction by competitive FP assay	ic50	2.2500	uM
(3S)-N-cyclopropyl-1-[3-[1-[(3-methoxyphenyl)sulfonylamino]-2-methyl-1-oxopropan-2-yl]oxyphenyl]-N-[(4-thiophen-2-ylphenyl)methyl]piperidine-3-carboxamide	1765112: Inhibition of full length C-terminal 6-His-tagged beta-catenin (1 to 781 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3)-N-terminal biotinylated human BCL9 (350 to 375 residues) protein-protein interaction incubated for 1 hr by Alphascreen assay	ki	2.3000	uM
2-(3,4-dihydroxyphenyl)-8-(4-fluorophenyl)-3,5,7-trihydroxychromen-4-one	2005038: Inhibition of full length beta-catenin (unknown origin)/FAM labeled BCL9 (350 to 375 residues) (unknown origin) protein-protein interaction by competitive FP assay	ic50	2.3500	uM
N-(3-aminopropyl)-2-[3-[(3R)-3-[[cyclopropyl-[[4-(1H-pyrazol-4-yl)phenyl]methyl]carbamoyl]amino]piperidin-1-yl]phenoxy]-2-methylpropanamide	2109718: Inhibition of full length his-tagged human beta-catenin (1 to 781 residues) expressed in Escherichia coli DE3/N-terminal FAM-tagged human BCL9 (350 to 375 residues) protein-protein interaction incubated for 2 hrs by fluorescence polarization assay	ic50	2.5900	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	1966239: Inhibition of beta-catenin/BCL9 protein-protein interaction in Wnt-dependent human HCT-116 cells assessed as reduction in Axin2 expression level by qRT-PCR assay	ic50	2.6900	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	2
Aflatoxin B1	increases methylation	2
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
dicrotophos	increases expression	1
bufotalin	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
nickel sulfate	increases expression	1
chromium hexavalent ion	increases expression	1
CGP 52608	affects binding, increases reaction	1
PKF115-584	increases expression	1
Irinotecan	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Matrines	decreases expression, decreases reaction, increases cleavage, increases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Atrazine	increases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Cannabidiol	increases expression	1
Coumestrol	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1

ChEMBL screening assays

125 unique, capped per target: 125 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4419383	Binding	Binding affinity to human BCL9 (350 to 375 residues) by ITC method	Substituted n-([1,1’’-biphenyl]-3-yl)-[1,1’’-biphenyl]-3-carboxamide analogs as inhibitors for beta-catenin/b-cell lymphoma 9 interactions

Cellosaurus cell lines

7 cell lines: 7 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_9489	CEMO-1	Cancer cell line	Male
CVCL_A083	YCUB-4	Cancer cell line	Male
CVCL_A084	YCUB-4R	Cancer cell line	Male
CVCL_D3ZJ	KCB9	Cancer cell line	Female
CVCL_D4AF	M4A1-M2B9	Cancer cell line	Male
CVCL_SF05	HAP1 BCL9 (-) 1	Cancer cell line	Male
CVCL_SF06	HAP1 BCL9 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease