NCOA3

Summary

NCOA3 (nuclear receptor coactivator 3, HGNC:7670) is a protein-coding gene on chromosome 20q13.12, encoding Nuclear receptor coactivator 3 (Q9Y6Q9). Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. It is a selective cancer dependency (DepMap: 30.3% of cell lines).

The protein encoded by this gene is a nuclear receptor coactivator that interacts with nuclear hormone receptors to enhance their transcriptional activator functions. The encoded protein has histone acetyltransferase activity and recruits p300/CBP-associated factor and CREB binding protein as part of a multisubunit coactivation complex. This protein is initially found in the cytoplasm but is translocated into the nucleus upon phosphorylation. Several transcript variants encoding different isoforms have been found for this gene. In addition, a polymorphic repeat region is found in the C-terminus of the encoded protein.

Source: NCBI Gene 8202 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 271 total — 3 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 30.3% of screened cell lines
• Transcription factor: yes — 82 downstream targets (CollecTRI)
• MANE Select transcript: NM_181659

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7670
Approved symbol	NCOA3
Name	nuclear receptor coactivator 3
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	RAC3, AIB1, ACTR, p/CIP, TRAM-1, CAGH16, TNRC16, KAT13B, bHLHe42, SRC-3, SRC3
Ensembl gene	ENSG00000124151
Ensembl biotype	protein_coding
OMIM	601937
Entrez	8202

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 22 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000371997, ENST00000371998, ENST00000372004, ENST00000490248, ENST00000497292, ENST00000888893, ENST00000888894, ENST00000888895, ENST00000888896, ENST00000888897, ENST00000888898, ENST00000888899, ENST00000888900, ENST00000888901, ENST00000888902, ENST00000888903, ENST00000888904, ENST00000938645, ENST00000938646, ENST00000938647, ENST00000938648, ENST00000938649, ENST00000938650, ENST00000943160

RefSeq mRNA: 4 — MANE Select: NM_181659 NM_001174087, NM_001174088, NM_006534, NM_181659

CCDS: CCDS13406, CCDS13407, CCDS54472

Canonical transcript exons

ENST00000371998 — 23 exons

Exon	Start	End
ENSE00000845234	47622229	47622330
ENSE00000845236	47625381	47625481
ENSE00000845240	47633496	47633636
ENSE00000845242	47635322	47635713
ENSE00000845243	47635891	47636762
ENSE00000845244	47637648	47637783
ENSE00000845245	47639008	47639202
ENSE00000845246	47639577	47639822
ENSE00000845247	47639925	47640051
ENSE00000845248	47642213	47642384
ENSE00000845253	47649005	47649109
ENSE00000845254	47650982	47651276
ENSE00000845258	47652406	47652580
ENSE00001151230	47623911	47624083
ENSE00001172838	47647073	47647366
ENSE00001388921	47634048	47634195
ENSE00001389011	47652931	47653072
ENSE00001456693	47583183	47583261
ENSE00001855854	47653406	47656872
ENSE00001935160	47501887	47502019
ENSE00003470504	47627922	47628023
ENSE00003539862	47627002	47627176
ENSE00003647487	47627561	47627749

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.7500 / max 1002.3256, expressed in 1816 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185088	49.7765	1811
185089	6.1893	1477
185087	3.0875	1196
185090	0.9207	378
185092	0.4559	205
209152	0.1889	90
185091	0.1312	60

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	99.02	gold quality
secondary oocyte	CL:0000655	98.91	gold quality
tendon of biceps brachii	UBERON:0008188	96.95	gold quality
epithelium of nasopharynx	UBERON:0001951	95.66	gold quality
buccal mucosa cell	CL:0002336	95.37	gold quality
oviduct epithelium	UBERON:0004804	95.06	gold quality
nipple	UBERON:0002030	95.01	gold quality
oocyte	CL:0000023	94.98	gold quality
cervix squamous epithelium	UBERON:0006922	94.89	gold quality
superficial temporal artery	UBERON:0001614	94.09	gold quality
esophagus squamous epithelium	UBERON:0006920	93.42	gold quality
bone marrow cell	CL:0002092	93.31	gold quality
tendon	UBERON:0000043	93.08	gold quality
oral cavity	UBERON:0000167	93.05	gold quality
cervix epithelium	UBERON:0004801	92.85	gold quality
palpebral conjunctiva	UBERON:0001812	92.74	gold quality
parotid gland	UBERON:0001831	92.73	gold quality
placenta	UBERON:0001987	92.42	gold quality
tonsil	UBERON:0002372	92.30	gold quality
epithelium of esophagus	UBERON:0001976	92.26	gold quality
pylorus	UBERON:0001166	91.93	gold quality
lymph node	UBERON:0000029	91.86	gold quality
squamous epithelium	UBERON:0006914	91.85	gold quality
lower lobe of lung	UBERON:0008949	91.83	gold quality
tongue squamous epithelium	UBERON:0006919	91.64	gold quality
calcaneal tendon	UBERON:0003701	91.50	gold quality
tibia	UBERON:0000979	91.07	gold quality
nasal cavity epithelium	UBERON:0005384	90.85	gold quality
colonic epithelium	UBERON:0000397	90.29	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.27	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	52.58
E-CURD-122	yes	19.29
E-MTAB-6678	yes	5.33
E-MTAB-6819	no	722.91
E-CURD-10	no	421.56
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

82 targets.

Target	Regulation
AKT1
AR	Activation
ATAD2
BCL2	Activation
BRCA1	Unknown
C4A
CACNA1E
CALCA
CARM1
CCDC80
CCND1	Activation
CCNE1
CDH17
CDK1
CDKN1A
CEL
CHUK
CREBBP
CYP1A1
CYP2B6
EP300
EPO	Activation
ERBB2	Unknown
ESR1
FCER1G
FLG	Activation
FLII
FSHB	Activation
GNRH1	Activation
GRIP1

Upstream regulators (CollecTRI, top): AR, E2F1, EHMT2, ESR1, FOXG1, GATA3, IRF8, MTA3, NCOA1, NCOA2, NCOA3, NCOR1, SP1

miRNA regulators (miRDB)

131 targeting NCOA3, 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-8485	100.00	77.57	4731
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 30.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• CAG/CAA repeat length in AIB1/SRC-3 gene may be associated with prosate cancer risk in Chinese men (PMID:11927493)
• the effect of STAT5b-RARalpha on the activity of myeloid transcription factors including STAT3, and STAT5 as well as its molecular interactions with the nuclear receptor corepressor, SMRT, and nuclear receptor coactivator, TRAM-1. (PMID:11929748)
• Results show that IKK-mediated phosphorylation of SRC-3 is a regulated event that plays an important role and also substantiate the role of SRC-3 in multiple signaling pathways. (PMID:11971985)
• SRC-3 has a role in the vasoprotective effects of estrogen and in cell migration, proliferation and cancers [review] (PMID:12650696)
• likely prognostic indicator for patients with breast tumors (PMID:12833450)
• AIB1 nuclear expression correlated with estrogen receptor alpha status in breast cancer; patients with AIB1 nuclear expression tended to be successfully treated by hormonal therapy (PMID:14503806)
• Polyglutamine repeat length in the AIB1 gene modifies breast cancer susceptibility in BRCA1 carriers (PMID:14648706)
• The polymorphic polyglutamine tract of the AIB1 gene is somatically unstable in breast cancer tissue and cell lines. (PMID:14684685)
• AIB1-Delta3 causes a significant increase in the efficacy of 17beta-estradiol at both estrogen receptor-alpha (ER-alpha) and ER-beta in ovarian, breast and endometrial cancer cell lines (PMID:14691461)
• HER2/Neu and ACTR may synergize to orchestrate mammary tumorigenesis through the dysregulation of the transcription factor ER81 and its target genes (PMID:14747462)
• results reveal an essential role of ACTR in control of breast cancer cell proliferation and implicate the ACTR-E2F1 pathway as a novel mechanism in antiestrogen resistance (PMID:15169882)
• AIB1 plays a dual role in regulating ERalpha activity, one in recruiting transcription factors including other coactivators involved in gene activation and the other in regulating ERalpha protein degradation mediated by the ubiquitin-proteosome machinery. (PMID:15289619)
• AIB1 has a major role in the multistage progression of pancreatic cancer (PMID:15448000)
• AIB1 is required for IGF-I-induced proliferation, signaling, cell survival, and gene expression in human breast cancer cells, independent of its role in estrogen receptor signaling (PMID:15548698)
• the N-terminally deleted isoform of AIB1 can play a role in breast cancer development and/or progression (PMID:15550471)
• The ability of SRC family coactivators to regulate the expression of one of these genes, PARD6B/Par6, was confirmed by using cells individually depleted of SRC-1. (PMID:15677324)
• Single Nucleotide Polymorphisms in NCOA3 is associated with breast cancer risk (PMID:15788663)
• There is no significant effect of AIB1 genetic variation on breast cancer risk in BRC1 or BRCA2 mutation carriers. (PMID:15900600)
• SRC-3 phosphorylation occurs only when either activated estrogen receptor alpha (ERalpha) or activated ERbeta is present. (PMID:16135815)
• SRC-3 coactivator protein-protein complex formation is modulated by Pin1. (PMID:16227615)
• Since AIB1 appears to modulate effect of endogenous hormones via the estrogen receptor, and smoking affects circulating hormone levels, results support evidence that steroid hormones play important role in breast carcinogenesis in BRCA1 mutation carriers (PMID:16244359)
• allelic variation at the NCOA3 locus may contribute to the genetic control of androgenic hormone and IGF levels and vertebral bone mass among older men (PMID:16263829)
• These studies reveal a novel role for SRC-3 in ovarian cancer progression by promoting cell migration, independently of its role in estrogen receptor signaling. (PMID:16298470)
• the AIB1 glutamine repeat does not substantially modify risk of breast cancer in BRCA1 and BRCA2 mutation carriers (PMID:16434590)
• Findings suggest a potential role of SRC-3 in the control of esophageal squamous cell carcinomas (ESCC) cell proliferation; such may be responsible, at least in part, for tumorigenesis and/or progression of ESCC. (PMID:16458427)
• ACTR has direct control of cell cycle gene expression; its autoregulation underlies its transforming activities. (PMID:16648476)
• poly Q encoding region of AIB1 gene is somatic unstable in breast cancer cell line (PMID:16670003)
• estrogen treatment led to increased phosphorylation and decreased sumoylation of AIB1; sumoylation coordinated with phosphorylation in regulating the transcriptional activity of AIB1 (PMID:16760465)
• There is a positive feedback regulatory loop consisting of E2F1 and SRC-3 to maintain high levels of SRC-3 and E2F1 activity, which may partially interpret the oncogenic role of SRC-3 overexpression. (PMID:16916939)
• androgen receptor and ACTR may play important roles in androgen ablation resistance by controlling key cell cycle gene expression (PMID:16921507)
• Results suggest that members of the SRC coactivator family, such as SRC-3, serve as substrates for the enzymatic coactivator coactivator-associated arginine methyltransferase 1 (CARM1). (PMID:16923966)
• Data show that downregulation of AIB1 by Mir-17-5p resulted in decreased estrogen receptor-mediated, as well as estrogen receptor-independent, gene expression and decreased proliferation of breast cancer cells. (PMID:16940181)
• Serum withdrawal or growth in high cell density caused rapid degradation of AIB1 protein, but not mRNA, in immortalized breast cancer cell lines. (PMID:16951183)
• nuclear receptor coactivator-3 has a role in primary cutaneous melanoma (PMID:17008696)
• p/CIP/SRC-3 activity and stability are regulated by CARM1-dependent methylation (PMID:17043108)
• Both DRIP205 and SRC-3 are required for the keratinocyte differentiation (PMID:17223341)
• the SRC3-myocardin interaction is a site of convergence for nuclear hormone receptor-mediated and VSMC-specific gene regulation (PMID:17360478)
• The overexpression of AIB1 may play a role in the carcinogenesis and development of gynecological cancers, especially ovarian cancers. (PMID:17441340)
• SRC-3 might be an important indicator of uterine endometrial cancer advancement and survival. (PMID:17532621)
• ubiquitination of SRC-3 is a phospho-mediated biphasic event and a transition from multi-(mono)ubiquitination (SRC-3 activation) to long-chain polyubiquitination (SRC-3 degradation) is processive during the coactivation of select transcription factors (PMID:17574025)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ncoa3	ENSDARG00000077404
mus_musculus	Ncoa3	ENSMUSG00000027678
rattus_norvegicus	Ncoa3	ENSRNOG00000005616
drosophila_melanogaster	tai	FBGN0041092

Paralogs (2): NCOA1 (ENSG00000084676), NCOA2 (ENSG00000140396)

Protein

Protein identifiers

Nuclear receptor coactivator 3 — Q9Y6Q9 (reviewed: Q9Y6Q9)

Alternative names: ACTR, Amplified in breast cancer 1 protein, CBP-interacting protein, Class E basic helix-loop-helix protein 42, Receptor-associated coactivator 3, Steroid receptor coactivator protein 3, Thyroid hormone receptor activator molecule 1

All UniProt accessions (2): Q9Y6Q9, Q0IIN7

UniProt curated annotations — full annotation on UniProt →

Function. Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Plays a central role in creating a multisubunit coactivator complex, which probably acts via remodeling of chromatin. Involved in the coactivation of different nuclear receptors, such as for steroids (GR and ER), retinoids (RARs and RXRs), thyroid hormone (TRs), vitamin D3 (VDR) and prostanoids (PPARs). Displays histone acetyltransferase activity. Also involved in the coactivation of the NF-kappa-B pathway via its interaction with the NFKB1 subunit.

Subunit / interactions. Present in a complex containing NCOA2, IKKA, IKKB, IKBKG and the histone acetyltransferase protein CREBBP. Found in a complex containing NCOA3, AR and MAK. Interacts with ATAD2; the interaction is enhanced by estradiol. Interacts with CARM1. Interacts with CASP8AP2. Interacts with CSNK1D. Interacts with DDX5. Interacts with ESR. Interacts with ESRRB; mediates the interaction between ESRRB and RNA polymerase II complexes and allows NCOA3 corecruitment to ESRRB, KLF4, NANOG, and SOX2 enhancer regions to trigger ESRRB-dependent gene activation involved in self-renewal and pluripotency. Interacts with NFKB1. Interacts with NPAS2. Interacts with NR3C1. Interacts with NR4A1/Nur77. Interacts with NR4A3. Interacts with PCAF. Interacts with PPARA. Interacts with PSMB9. Interacts with RARA. Interacts with RXRA. Interacts with THRA. Interacts with VDR.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed. High expression in heart, skeletal muscle, pancreas and placenta. Low expression in brain, and very low in lung, liver and kidney.

Post-translational modifications. Acetylated by CREBBP. Acetylation occurs in the RID domain, and disrupts the interaction with nuclear receptors and regulates its function. Methylated by CARM1. Phosphorylated by IKK complex. Regulated its function. Phosphorylation at Ser-601 by CK1 promotes coactivator function.

Activity regulation. Coactivator activity on nuclear receptors and NF-kappa-B pathways is enhanced by various hormones, and the TNF cytokine, respectively. TNF stimulation probably enhances phosphorylation, which in turn activates coactivator function. In contrast, acetylation by CREBBP apparently suppresses coactivation of target genes by disrupting its association with nuclear receptors. Binds to CSNK1D.

Domain organisation. Contains three Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. Motifs 1 and 2 are essential for the association with nuclear receptors, and constitute the RID domain (Receptor-interacting domain).

Polymorphism. The length of the poly-Gln region is polymorphic in the normal population.

Miscellaneous. NCOA3 is frequently amplified or overexpressed in breast and ovarian cancers.

Similarity. Belongs to the SRC/p160 nuclear receptor coactivator family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9Y6Q9-1	1	yes
Q9Y6Q9-2	2
Q9Y6Q9-3	3
Q9Y6Q9-4	4
Q9Y6Q9-5	5

RefSeq proteins (4): NP_001167558, NP_001167559, NP_006525, NP_858045* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR009110	Nuc_rcpt_coact	Homologous_superfamily
IPR010011	NCO_DUF1518	Domain
IPR011598	bHLH_dom	Domain
IPR013767	PAS_fold	Domain
IPR014920	Nuc_rcpt_coact_Ncoa-typ	Domain
IPR014935	SRC/p160_LXXLL	Domain
IPR017426	Nuclear_rcpt_coactivator	Family
IPR032565	NCOA2/3_DUF4927	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR037077	Nuc_rcpt_coact_Ncoa_int_sf	Homologous_superfamily
IPR056193	bHLH_NCOA1-3	Domain
IPR056194	NCOA3_bHLH	Domain

Pfam: PF00989, PF07469, PF08815, PF08832, PF14598, PF16279, PF16665, PF23172

Enzyme classification (BRENDA):

• EC 2.3.1.48 — histone acetyltransferase (BRENDA: 41 organisms, 681 substrates, 1134 inhibitors, 140 Km, 96 kcat entries)

Substrate kinetics (BRENDA)

27 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-COA	0.0002–0.046	51
HISTONE H3	0.007–2.09	23
HISTONE H4	—	11
HISTONE H4 PEPTIDE	0.0208–0.197	7
HISTONE	0.075–1.4	6
HISTONE H3 TAIL PEPTIDE	0.044–0.112	4
PICCOLONUA4 PEPTIDE	0.135–0.372	4
3-AZIDOPROPIONYL-COA	0.0002–0.0086	3
4-PENTYNOYL-COA	0.0009–0.0859	3
SPERMIDINE	0.18–0.27	3
5-HEXYNOYL-COA	0.0006–0.0117	2
6-HEPTYNOYL-COA	0.0003–0.0237	2
HISTONE H3-PEPTIDE	0.05–0.49	2
PROTEIN P53	1.28–4.63	2
3-AZIDOPROPANOYL-COA	0.0103	1

Catalyzed reactions (Rhea), 1 shown:

• L-lysyl-[protein] + acetyl-CoA = N(6)-acetyl-L-lysyl-[protein] + CoA + H(+) (RHEA:45948)

UniProt features (74 total): modified residue 19, sequence variant 11, region of interest 10, compositionally biased region 9, mutagenesis site 7, helix 6, splice variant 4, short sequence motif 3, domain 2, initiator methionine 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3L3X	X-RAY DIFFRACTION	1.55
9HFW	X-RAY DIFFRACTION	1.7
3L3Z	X-RAY DIFFRACTION	2
6SQC	X-RAY DIFFRACTION	2.28
1KBH	SOLUTION NMR
6ES7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6Q9-F1	49.26	0.10

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 (19): 2, 214, 551, 569, 601, 616, 619, 620, 687, 694, 728, 857, 860, 867, 1033, 1171, 1177, 1188, 1330

Mutagenesis-validated functional residues (7):

Position	Phenotype
616	strongly reduces acetylation by crebbp.
619–620	abolishes acetylation by crebbp.
647	does not affect acetylation by crebbp.
681	does not affect acetylation by crebbp.
687	does not affect acetylation by crebbp.
700	does not affect acetylation by crebbp.
708	does not affect acetylation by crebbp.

Function

Pathways and Gene Ontology

Reactome pathways

21 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-162582	Signal Transduction
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-556833	Metabolism of lipids
R-HSA-5619507	Activation of HOX genes during differentiation
R-HSA-5683057	MAPK family signaling cascades
R-HSA-74160	Gene expression (Transcription)
R-HSA-8939211	ESR-mediated signaling
R-HSA-9006931	Signaling by Nuclear Receptors
R-HSA-9818564	Epigenetic regulation of gene expression by MLL3 and MLL4 complexes
R-HSA-9843745	Adipogenesis
R-HSA-9851695	Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes
R-HSA-9917777	Epigenetic regulation by WDR5-containing histone modifying complexes

MSigDB gene sets: 714 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_FOREBRAIN_NEURON_DEVELOPMENT, REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, TGGTGCT_MIR29A_MIR29B_MIR29C, MODULE_52, GOBP_EPITHELIUM_DEVELOPMENT, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_REGULATION_OF_CELL_MATURATION, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_RESPONSE_TO_ESTRADIOL, GOBP_CELL_CHEMOTAXIS, LU_IL4_SIGNALING

GO Biological Process (12): cellular response to hormone stimulus (GO:0032870), cell dedifferentiation (GO:0043697), positive regulation of keratinocyte differentiation (GO:0045618), positive regulation of transcription by RNA polymerase II (GO:0045944), retinoic acid receptor signaling pathway (GO:0048384), vitamin D receptor signaling pathway (GO:0070561), cellular response to estradiol stimulus (GO:0071392), positive regulation of stem cell population maintenance (GO:1902459), regulation of stem cell division (GO:2000035), chromatin remodeling (GO:0006338), regulation of DNA-templated transcription (GO:0006355), nuclear protein quality control by the ubiquitin-proteasome system (GO:0071630)

GO Molecular Function (12): RNA polymerase II complex binding (GO:0000993), transcription coactivator activity (GO:0003713), histone acetyltransferase activity (GO:0004402), nuclear receptor binding (GO:0016922), nuclear thyroid hormone receptor binding (GO:0046966), protein dimerization activity (GO:0046983), disordered domain specific binding (GO:0097718), transcription coregulator activity (GO:0003712), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746), protein-lysine-acetyltransferase activity (GO:0061733)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Developmental Biology	2
Signal Transduction	2
Regulation of lipid metabolism by PPARalpha	1
Adipogenesis	1
Activation of HOX genes during differentiation	1
MAPK family signaling cascades	1
ESR-mediated signaling	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
Gene expression (Transcription)	1
Metabolism of lipids	1
Metabolism	1
Signaling by Nuclear Receptors	1
Epigenetic regulation by WDR5-containing histone modifying complexes	1
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
positive regulation of multicellular organismal process	2
positive regulation of DNA-templated transcription	2
hormone-mediated signaling pathway	2
nuclear receptor-mediated signaling pathway	2
response to hormone	1
cellular response to chemical stimulus	1
cellular response to endogenous stimulus	1
dedifferentiation	1
cellular developmental process	1
keratinocyte differentiation	1
positive regulation of epidermal cell differentiation	1
regulation of keratinocyte differentiation	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
cellular response to vitamin D	1
response to estradiol	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
stem cell population maintenance	1
positive regulation of developmental process	1
regulation of stem cell population maintenance	1
stem cell division	1
regulation of cell division	1
chromatin organization	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
protein quality control for misfolded or incompletely synthesized proteins	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
cellular response to misfolded protein	1
RNA polymerase core enzyme binding	1
transcription coregulator activity	1
protein-lysine-acetyltransferase activity	1
histone modifying activity	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
nuclear receptor binding	1
protein binding	1
protein domain specific binding	1
transcription regulator activity	1

Protein interactions and networks

STRING

2330 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NCOA3	ESR1	P03372	997
NCOA3	EP300	Q09472	993
NCOA3	CREBBP	Q92793	989
NCOA3	NCOA2	Q15596	955
NCOA3	HEATR6	Q6AI08	934
NCOA3	PSME3	P61289	917
NCOA3	CARM1	Q86X55	883
NCOA3	KAT2B	Q92831	878
NCOA3	NCOA1	Q15788	863
NCOA3	AR	P10275	822
NCOA3	ESR2	Q92731	817
NCOA3	TIA1	P31483	815
NCOA3	PGR	P06401	813
NCOA3	NCOR1	O75376	809
NCOA3	PRMT1	Q99873	800

IntAct

145 interactions, top by confidence:

A	B	Type	Score
ESR1	PGR	psi-mi:“MI:0915”(physical association)	0.770
NCOA3	SPOP	psi-mi:“MI:0915”(physical association)	0.740
SPOP	NCOA3	psi-mi:“MI:0407”(direct interaction)	0.740
NCOA3	SPOP	psi-mi:“MI:0407”(direct interaction)	0.740
SPOP	NCOA3	psi-mi:“MI:0915”(physical association)	0.740
NCOA3	SPOP	psi-mi:“MI:0914”(association)	0.740
SPOP	NCOA3	psi-mi:“MI:2364”(proximity)	0.740
NCOA3	SPOP	psi-mi:“MI:2364”(proximity)	0.740
ESR1	NCOA3	psi-mi:“MI:0915”(physical association)	0.690
NFIC	NFIB	psi-mi:“MI:2364”(proximity)	0.690
ESR1	TRIM24	psi-mi:“MI:0914”(association)	0.640
NCOA3	CARM1	psi-mi:“MI:0914”(association)	0.620
NCOA3	CARM1	psi-mi:“MI:0915”(physical association)	0.620
NCOA3	PSME3	psi-mi:“MI:0915”(physical association)	0.600

BioGRID (414): NCOA3 (Reconstituted Complex), NCOA3 (Affinity Capture-Western), NCOA3 (Protein-peptide), NCOA3 (Affinity Capture-Western), HIST4H4 (Biochemical Activity), HIST3H3 (Biochemical Activity), ETV1 (Biochemical Activity), NCOA3 (Biochemical Activity), ESR1 (Reconstituted Complex), NCOA3 (Reconstituted Complex), NCOA3 (Reconstituted Complex), NCOA3 (Reconstituted Complex), NCOA3 (Reconstituted Complex), NCOA3 (Reconstituted Complex), NCOA3 (Reconstituted Complex)

ESM2 similar proteins: A0A3Q7JC00, A0JM64, A0JNC2, A2VE44, A4IHD9, B2C6R6, B5DE09, B8BCZ8, E7F1H9, F4JT98, O09000, O57539, P78364, Q0WVM7, Q15596, Q17BA4, Q2NLB0, Q3TCX3, Q5RDA3, Q5TP13, Q5ZL54, Q61026, Q64028, Q6GP15, Q6K271, Q6NS15, Q6PEH8, Q71SY5, Q7XYY2, Q7ZVN7, Q80TM6, Q8C7E9, Q8CHY6, Q8HXM1, Q8IZL2, Q8VCB2, Q8W234, Q90WJ3, Q924H2, Q940A7

Diamond homologs: A9YTQ3, B5DE09, O02747, O09000, O15945, O57539, P30561, P35869, P41738, P70365, P97459, Q15596, Q15788, Q3U1U7, Q4PJW2, Q61026, Q8IXF0, Q8R4S2, Q8R4S4, Q8R4S5, Q8R4S6, Q8R4S7, Q95LD9, Q98TW1, Q99742, Q9EPU2, Q9QZQ0, Q9W705, Q9WUI9, Q9Y6Q9, A0MLS5, O00327, O08785, O15516, O61735, O88529, P97460, Q5R4T2, Q5RAK8, Q5ZQU2

SIGNOR signaling

25 interactions.

A	Effect	B	Mechanism
CHUK	up-regulates	NCOA3	phosphorylation
PRKACA	up-regulates	NCOA3	phosphorylation
NCOA3	“up-regulates quantity by expression”	CCND1	“transcriptional regulation”
ABL1	up-regulates	NCOA3	phosphorylation
CSNK1D	up-regulates	NCOA3	phosphorylation
CDK1	down-regulates	NCOA3	phosphorylation
MAPK6	up-regulates	NCOA3	phosphorylation
CyclinB/CDK1	down-regulates	NCOA3	phosphorylation
MAPK14	“up-regulates activity”	NCOA3	phosphorylation
IKBKB	“up-regulates activity”	NCOA3	phosphorylation
SPOP	“down-regulates quantity by destabilization”	NCOA3	binding
PFKFB4	“up-regulates activity”	NCOA3	phosphorylation
“Cullin 7-RBX1-Skp1”	“down-regulates quantity by destabilization”	NCOA3	ubiquitination
DYRK3	“down-regulates activity”	NCOA3	phosphorylation
NCOA3	“up-regulates activity”	ATF4	binding
SCF-FBW7	“down-regulates quantity by destabilization”	NCOA3	ubiquitination
GSK3A	“down-regulates quantity by destabilization”	NCOA3	phosphorylation
CHKA	“down-regulates quantity by destabilization”	NCOA3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 112 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
BMAL1:CLOCK,NPAS2 activates circadian expression	5	29.0×	2e-05
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	5	27.9×	2e-05
SUMOylation of intracellular receptors	6	27.6×	3e-06
R-HSA-400253	5	23.7×	4e-05
Deactivation of the beta-catenin transactivating complex	7	22.4×	2e-06
Nuclear Receptor transcription pathway	8	22.0×	3e-07
Expression of BMAL (ARNTL), CLOCK, and NPAS2	5	20.1×	8e-05
Transcriptional regulation of white adipocyte differentiation	11	19.6×	4e-09

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of miRNA transcription	6	40.7×	8e-07
neuron fate specification	5	38.2×	2e-05
positive regulation of miRNA transcription	8	25.3×	2e-07
canonical NF-kappaB signal transduction	6	23.9×	2e-05
mRNA transcription by RNA polymerase II	6	21.6×	3e-05
inner ear morphogenesis	5	16.4×	6e-04
somatic stem cell population maintenance	6	16.2×	1e-04
cartilage development	5	13.7×	9e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	6
Uncertain significance	195
Likely benign	26
Benign	2

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1185585	NM_181659.3(NCOA3):c.2810C>G (p.Ser937Cys)	Pathogenic
1723153	NM_005052.3(RAC3):c.183GGA[1] (p.Glu62del)	Pathogenic
425149	NM_005052.3(RAC3):c.184G>A (p.Glu62Lys)	Pathogenic
2583144	NM_005052.3(RAC3):c.86C>G (p.Pro29Arg)	Likely pathogenic
2663816	NM_005052.3(RAC3):c.276T>A (p.Asn92Lys)	Likely pathogenic
3347558	NM_005052.3(RAC3):c.193G>A (p.Asp65Asn)	Likely pathogenic
871529	NM_005052.3(RAC3):c.187G>A (p.Asp63Asn)	Likely pathogenic
977758	NM_005052.3(RAC3):c.34G>C (p.Gly12Arg)	Likely pathogenic
982386	NM_005052.3(RAC3):c.191A>G (p.Tyr64Cys)	Likely pathogenic

SpliceAI

5273 predictions. Top by Δscore:

Variant	Effect	Δscore
17:82031795:GG:G	donor_gain	1.0000
17:82031796:GG:G	donor_gain	1.0000
17:82031797:G:GG	donor_gain	1.0000
17:82031798:T:A	donor_loss	1.0000
17:82032441:A:T	donor_gain	1.0000
17:82032699:ACT:A	acceptor_gain	1.0000
17:82032701:T:A	acceptor_gain	1.0000
17:82032708:CAGTT:C	acceptor_loss	1.0000
17:82032709:A:AG	acceptor_gain	1.0000
17:82032709:AGTTT:A	acceptor_loss	1.0000
17:82032710:G:GA	acceptor_gain	1.0000
17:82032710:GT:G	acceptor_gain	1.0000
17:82032710:GTT:G	acceptor_gain	1.0000
17:82032710:GTTT:G	acceptor_gain	1.0000
17:82032710:GTTTT:G	acceptor_gain	1.0000
17:82032787:G:GT	donor_gain	1.0000
17:82032824:AAACT:A	donor_gain	1.0000
17:82032825:AACT:A	donor_gain	1.0000
17:82032826:ACT:A	donor_gain	1.0000
17:82032826:ACTG:A	donor_loss	1.0000
17:82032827:CT:C	donor_gain	1.0000
17:82032827:CTGTA:C	donor_loss	1.0000
17:82032829:GTAC:G	donor_gain	1.0000
17:82033435:TGCA:T	acceptor_loss	1.0000
17:82033437:CAGTG:C	acceptor_loss	1.0000
17:82033438:A:AG	acceptor_gain	1.0000
17:82033438:AGT:A	acceptor_gain	1.0000
17:82033438:AGTG:A	acceptor_gain	1.0000
17:82033439:G:GA	acceptor_gain	1.0000
17:82033439:GT:G	acceptor_gain	1.0000

AlphaMissense

9486 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:47623970:T:C	L48S	1.000
20:47623972:G:C	A49P	1.000
20:47623979:T:C	L51P	1.000
20:47624042:T:C	L72S	1.000
20:47625474:T:C	L117S	1.000
20:47625477:T:C	L118P	1.000
20:47627011:G:C	G123R	1.000
20:47627012:G:A	G123D	1.000
20:47627014:T:C	F124L	1.000
20:47627015:T:C	F124S	1.000
20:47627016:C:A	F124L	1.000
20:47627016:C:G	F124L	1.000
20:47627018:T:C	L125P	1.000
20:47627050:T:C	F136L	1.000
20:47627052:T:A	F136L	1.000
20:47627052:T:G	F136L	1.000
20:47627054:T:A	V137E	1.000
20:47627066:T:A	V141D	1.000
20:47627078:T:C	L145P	1.000
20:47627099:T:C	L152P	1.000
20:47627114:T:A	V157D	1.000
20:47627704:T:C	C226R	1.000
20:47627707:T:C	F227L	1.000
20:47627709:T:A	F227L	1.000
20:47627709:T:G	F227L	1.000
20:47627942:T:C	C248R	1.000
20:47627944:T:G	C248W	1.000
20:47627949:C:A	A250E	1.000
20:47627952:G:C	R251P	1.000
20:47628000:T:C	F267S	1.000

dbSNP variants (sampled 300 via entrez): RS1000007199 (20:47502231 A>C,G), RS1000009035 (20:47544456 A>G), RS1000093218 (20:47582465 G>A), RS1000095903 (20:47626857 A>T), RS1000110609 (20:47595084 G>A,T), RS1000118025 (20:47530904 G>A), RS1000119062 (20:47610382 G>A), RS1000209025 (20:47521691 C>A,T), RS1000211960 (20:47520040 G>A), RS1000221250 (20:47525498 C>T), RS1000234296 (20:47530541 C>T), RS1000273558 (20:47526169 C>T), RS1000292766 (20:47641038 A>G), RS1000293708 (20:47568101 A>T), RS1000306339 (20:47574839 T>G)

Disease associations

OMIM: gene MIM:601937 | disease phenotypes: MIM:618577

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with structural brain anomalies and dysmorphic facies	Strong	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Limited	Autosomal dominant

Mondo (3): neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (MONDO:0032820), intellectual disability (MONDO:0001071), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (2): Facial dysmorphism-global developmental delay-hypotonia-polymicrogyria syndrome (Orphanet:659609), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000289	Broad philtrum
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000520	Proptosis
HP:0000527	Long eyelashes
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001357	Plagiocephaly
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002650	Scoliosis
HP:0003049	Ulnar deviation of the wrist
HP:0003196	Short nose
HP:0010864	Severe intellectual disability
HP:0011320	Unilambdoid synostosis
HP:0011800	Midface retrusion
HP:0011968	Feeding difficulties
HP:0012815	Hypoplastic female external genitalia
HP:0030084	Clinodactyly

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000323_3	Response to treatment for acute lymphoblastic leukemia	2.000000e-06
GCST002155_4	Osteoarthritis (hip)	2.000000e-10
GCST010002_133	Refractive error	2.000000e-50
GCST010241_61	Apolipoprotein A1 levels	3.000000e-14
GCST010242_454	HDL cholesterol levels	7.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL1615382 (SINGLE PROTEIN), CHEMBL2095161 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195515 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195551 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 941,288 (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
CHEMBL34259	METHOTREXATE	4	398,396
CHEMBL44657	ETOPOSIDE	4	226,069
CHEMBL803	CYTARABINE	4	202,889
CHEMBL405110	METHYLENE BLUE ANHYDROUS	4	113,934

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs115501901	NCOA3		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 2.3.1.48 Histone acetyltransferases (HATs)

Binding affinities (BindingDB)

97 measured of 339 human assays (349 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
2-(benzylsulfanyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile	IC50	25.4 nM
2,5-bis(chloranyl)-3-[2-(dimethylamino)-1,3-thiazol-5-yl]-6-pyrrolidin-1-yl-cyclohexa-2,5-diene-1,4-dione	EC50	210 nM
4-amino-3-(4-methylphenyl)-5-[(4-methyl-1-piperazinyl)carbonyl]-1,3-thiazole-2(3H)-thione	IC50	250 nM
3,4-dimethyl-N-(5-thiophen-2-yl-1,3,4-thiadiazol-2-yl)benzamide	EC50	786 nM
5-bromanyl-N-(4-piperidin-1-ylphenyl)pyridine-3-carboxamide	EC50	1020 nM
1-[[1-(4-methoxyphenyl)-3-pyrrolidinyl]methyl]-3-phenylurea	IC50	2580 nM
2-(2-Adamantan-1-yl-2-oxo-ethylsulfanyl)-6-amino-4-(4-chloro-phenyl)-pyridine-3,5-dicarbonitrile	EC50	2940 nM
4-[(2-benzoxybenzyl)amino]phenol	EC50	2980 nM
MLS000107751	EC50	3570 nM
2-(4-chloranyl-3-methyl-phenoxy)-N-[2-methyl-5-(3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)phenyl]ethanamide	IC50	4880 nM
MLS000560834	EC50	6080 nM
(7-Cyano-[1,3]dioxolo[4,5-g]quinolin-6-ylsulfanyl)-acetic acid methyl ester	EC50	7890 nM
2-[(3,4-dimethoxyphenyl)-oxomethyl]imino-3,4-dimethyl-5-thiazolecarboxylic acid ethyl ester	EC50	8100 nM
MLS000040305	EC50	8460 nM
2-[[1-(3,5-dimethoxyphenyl)-1,2,3,4-tetrazol-5-yl]sulfanyl]-N-(4-ethanoylphenyl)ethanamide	EC50	8560 nM
3-[(5-bromothiophene-2-carbonyl)amino]thiophene-2-carboxylic acid methyl ester	EC50	8670 nM
4-bromanyl-N-(1-propylbenzimidazol-2-yl)benzamide	EC50	8960 nM
2-[2-(2-chlorophenyl)-4-phenyl-1,3-thiazol-5-yl]-N-phenyl-ethanamide	EC50	10000 nM
2-[3-Cyano-6-(4-methoxy-phenyl)-4-thiophen-2-yl-pyridin-2-ylsulfanyl]-N-(2-methoxy-benzyl)-acetamide	EC50	10300 nM
10-methoxy-5H-[1]benzothiolo[2,3-c]quinolin-6-one	EC50	11000 nM
2-[(6-amino-3,5-dicyano-4-p-phenetyl-2-pyridyl)thio]acetic acid butyl ester	IC50	11000 nM
2-[(3-methoxyphenyl)-oxomethyl]imino-3,4-dimethyl-5-thiazolecarboxylic acid ethyl ester	EC50	11000 nM
2-[2-(3-chlorobenzothiophene-2-carbonyl)imino-6-sulfamoyl-1,3-benzothiazol-3-yl]acetic acid ethyl ester	EC50	11200 nM
3-(4-Chloro-phenyl)-1-cyclopropyl-1-(7-ethyl-1,2,3,9b-tetraaza-cyclopenta[a]naphthalen-4-ylmethyl)-thiourea	EC50	11500 nM
(7-Cyano-[1,3]dioxolo[4,5-g]quinolin-6-ylsulfanyl)-acetic acid isopropyl ester	EC50	11900 nM
5-[[4-(4-methylpiperidino)sulfonylbenzoyl]oxymethyl]furan-2-carboxylic acid methyl ester	EC50	12600 nM
2-[[5-(1-benzofuran-2-yl)-4-methyl-1,2,4-triazol-3-yl]sulfanyl]-N-(3-bromophenyl)acetamide	EC50	13300 nM
2,5-bis(chloranyl)-N-[3-(2-ethoxyethyl)-6-sulfamoyl-1,3-benzothiazol-2-ylidene]thiophene-3-carboxamide	EC50	13400 nM
2-[4-(1,3-benzothiazol-2-yl)-1-piperazinyl]-4-methoxy-1,3-benzothiazole	EC50	13400 nM
2-({5-[2-(4-bromophenyl)-2-oxoethyl]-3-cyano-4,6-dimethyl-2-pyridinyl}sulfanyl)-N-(4-fluorophenyl)acetamide	EC50	13800 nM
MLS000543203	EC50	14400 nM
2-[2-oxidanylidene-2-(2-oxidanylidenechromen-3-yl)ethyl]sulfanyl-6-phenyl-pyridine-3-carbonitrile	EC50	15500 nM
4-[[4-(4-chlorophenyl)-3-cyano-6-phenyl-2-pyridinyl]thio]-3-oxobutanoic acid ethyl ester	EC50	16400 nM
N-(4-(4-(azepan-1-ylsulfonyl)phenyl)thiazol-2-yl)thiophene-2-carboxamide	EC50	16500 nM
6-(4-fluorophenyl)-3-methyl-N-(6-methyl-2-pyridinyl)-2-imidazo[2,1-b]thiazolecarboxamide	EC50	16800 nM
2-(1,3-benzoxazol-2-ylsulfanyl)-1-(3,4,5-trimethoxyphenyl)ethanone	EC50	16900 nM
4-[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]-N-prop-2-enyl-benzamide	EC50	17100 nM
4-fluoranyl-N-(2-phenylquinazolin-4-yl)benzamide	EC50	17200 nM
5-bromanyl-N-(phenylcarbamothioyl)furan-2-carboxamide	EC50	17600 nM
4-methyl-N-(4-pyrrolidin-1-ylphenyl)benzamide	IC50	17900 nM
2-(4-isopropoxybenzoyl)imino-3,4-dimethyl-4-thiazoline-5-carboxylic acid ethyl ester	EC50	18300 nM
6-amino-5-[1-(4-chlorophenyl)-3-methyl-thieno[2,3-c]pyrazole-5-carbonyl]-1,3-dimethyl-pyrimidine-2,4-quinone	EC50	18400 nM
5-chloranyl-N-(4-methoxy-3-prop-2-ynyl-1,3-benzothiazol-2-ylidene)thiophene-2-carboxamide	EC50	18400 nM
2-[3-cyano-6-(4-methoxyphenyl)-4-thiophen-2-yl-pyridin-2-yl]sulfanyl-N-(phenylmethyl)ethanamide	EC50	18800 nM
2-(3-Cyano-6-methyl-quinolin-2-ylsulfanyl)-N-thiophen-2-ylmethyl-acetamide	EC50	19000 nM
2-(3-bromophenyl)-4-quinolinecarboxylic acid [2-[3-(dimethylsulfamoyl)anilino]-2-oxoethyl] ester	EC50	19100 nM
3,6-bis(chloranyl)-1-[2-[[3-chloranyl-5-(trifluoromethyl)pyridin-2-yl]amino]ethyl]quinoxalin-2-one	EC50	19800 nM
1-(1,3-benzodioxol-5-ylmethyl)-3-(2,1,3-benzothiadiazol-5-yl)urea	EC50	20400 nM
4-(4-{[4-cyclohexyl-3-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)-2-methylbut-3-yn-2-ol	IC50	21200 nM
3-chloro-1-benzothiophene-2-carboxylic acid [2-[(3,5-dichloro-2-pyridinyl)amino]-2-oxoethyl] ester	EC50	21600 nM

ChEMBL bioactivities

184 potent at pChembl≥5 of 359 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.73	IC50	18.61	nM	CHEMBL132431
7.04	IC50	91.26	nM	CHEMBL1571037
6.68	IC50	211	nM	METHOTREXATE
6.43	IC50	374.7	nM	ETOPOSIDE
6.36	IC50	434.1	nM	CHEMBL1699187
6.30	IC50	503.1	nM	CHEMBL1373969
6.28	IC50	521.9	nM	CHEMBL1705854
6.18	IC50	660.6	nM	CHEMBL1713127
6.16	IC50	694.3	nM	CHEMBL1611106
6.12	IC50	762.3	nM	CHEMBL1306377
6.02	IC50	950	nM	CHEMBL59530
6.00	IC50	1008	nM	CHEMBL1713613
5.99	IC50	1016	nM	CHEMBL1444434
5.98	IC50	1049	nM	CHEMBL1445386
5.97	IC50	1072	nM	CHEMBL1302818
5.97	IC50	1077	nM	CHEMBL1475299
5.92	IC50	1197	nM	CHEMBL1413178
5.89	IC50	1279	nM	CHEMBL1608402
5.88	IC50	1315	nM	IRINOTECAN HYDROCHLORIDE HYDRATE
5.86	IC50	1378	nM	CHEMBL1612809
5.86	IC50	1386	nM	CHEMBL1307972
5.84	IC50	1444	nM	CHEMBL1383315
5.80	IC50	1575	nM	CHEMBL1370927
5.80	IC50	1583	nM	CHEMBL1469670
5.76	IC50	1744	nM	CHEMBL1418980
5.68	IC50	2090	nM	CHEMBL1399772
5.68	IC50	2091	nM	CHEMBL1965654
5.67	IC50	2128	nM	CHEMBL1421781
5.67	IC50	2136	nM	CHEMBL1412433
5.67	IC50	2116	nM	CHEMBL1400379
5.64	IC50	2299	nM	CHEMBL494325
5.61	IC50	2458	nM	CHEMBL1502254
5.59	IC50	2568	nM	CHEMBL2005690
5.58	IC50	2634	nM	CHEMBL1535999
5.58	IC50	2615	nM	CHEMBL1528507
5.58	IC50	2621	nM	CHEMBL1456725
5.57	IC50	2669	nM	CHEMBL1398705
5.57	IC50	2695	nM	CHEMBL1471916
5.56	IC50	2751	nM	CHEMBL1610875
5.55	IC50	2810	nM	CHEMBL1318140
5.54	IC50	2893	nM	CHEMBL533226
5.54	IC50	2870	nM	CHEMBL1469961
5.52	IC50	2991	nM	CHEMBL356169
5.51	EC50	3056	nM	METHYLENE BLUE ANHYDROUS
5.51	IC50	3108	nM	CHEMBL1406398
5.51	IC50	3109	nM	CHEMBL1368216
5.50	IC50	3161	nM	CHEMBL1480880
5.49	EC50	3261	nM	CHEMBL1359775
5.49	IC50	3236	nM	CHEMBL1427335
5.49	IC50	3211	nM	CHEMBL1605666

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases reaction, increases activity, affects binding, increases expression, decreases expression (+4 more)	20
Tamoxifen	affects reaction, decreases response to substance, increases expression, increases phosphorylation, affects binding (+2 more)	6
Tetrachlorodibenzodioxin	increases expression, decreases reaction, decreases expression, affects binding, increases reaction (+2 more)	6
Tretinoin	increases expression, decreases reaction, increases degradation, affects binding, increases reaction (+2 more)	6
Valproic Acid	affects cotreatment, decreases expression, increases expression	5
trichostatin A	affects expression, affects cotreatment, decreases expression	4
Benzo(a)pyrene	decreases expression	4
bisphenol A	affects binding, affects folding, affects reaction, decreases expression, increases expression (+1 more)	3
Resveratrol	affects cotreatment, decreases reaction, increases reaction, increases expression, decreases expression (+1 more)	3
Calcitriol	increases response to substance, affects binding, increases reaction, increases activity	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	3
arsenite	affects binding, decreases reaction, increases expression	2
bisphenol S	increases reaction, affects binding, affects folding, decreases reaction	2
(+)-JQ1 compound	affects binding, affects reaction, increases reaction, decreases reaction, increases expression	2
bisphenol AF	affects binding, affects folding, affects reaction, increases reaction	2
Fulvestrant	affects binding, affects cotreatment, decreases reaction, increases reaction, increases expression	2
Copper	affects binding, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Metribolone	affects binding, affects folding, affects reaction, decreases reaction, increases activity	2
Genistein	increases reaction, decreases expression, affects binding	2
Raloxifene Hydrochloride	increases reaction, affects binding	2
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
butamben	affects binding, increases reaction	1
testosterone enanthate	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
kaempferol	affects binding, increases reaction	1

ChEMBL screening assays

42 unique, capped per target: 39 binding, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1963969	Functional	PUBCHEM_BIOASSAY: Counterscreen for inhibitors of the Steroid Receptor Coactivator 1 (SRC1; NCOA1): Luminescence-based cell-based high throughput dose response assay to identify inhibitors of the Steroid Receptor Coactivator 3 (SRC3; NCOA3)	PubChem BioAssay data set
CHEMBL5546337	Binding	Inhibition of recombinant His-tagged SRC-3 (unknown origin) expressed in baculovirus assessed as reduction in recruitment of SRC-3 in ER complex at 0.15 uM incubated for 30 mins by pull-down based western blotting analysis	Lead Compound Development of SRC-3 Inhibitors with Improved Pharmacokinetic Properties and Anticancer Efficacy. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0UL	Ubigene Hep G2 NCOA3 KO	Cancer cell line	Male
CVCL_E0YF	Ubigene MCF-7 NCOA3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

197 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
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
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders