ESRRB

Summary

ESRRB (estrogen related receptor beta, HGNC:3473) is a protein-coding gene on chromosome 14q24.3, encoding Steroid hormone receptor ERR2 (O95718). Transcription factor that binds a canonical ESRRB recognition (ERRE) sequence 5’TCAAGGTCA-3’ localized on promoter and enhancer of targets genes regulating their expression or their transcription activity.

This gene encodes a protein with similarity to the estrogen receptor. Its function is unknown; however, a similar protein in mouse plays an essential role in placental development.

Source: NCBI Gene 2103 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 332 total — 11 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Transcription factor: yes — 12 downstream targets (CollecTRI)
• MANE Select transcript: NM_001379180

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3473
Approved symbol	ESRRB
Name	estrogen related receptor beta
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Aliases	ERR2, ERRbeta, NR3B2, ERRb
Ensembl gene	ENSG00000119715
Ensembl biotype	protein_coding
OMIM	602167
Entrez	2103

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000380887, ENST00000505752, ENST00000509242, ENST00000509323, ENST00000512784, ENST00000556177, ENST00000611036, ENST00000644823

RefSeq mRNA: 3 — MANE Select: NM_001379180 NM_001379180, NM_001411038, NM_004452

CCDS: CCDS91909, CCDS91910, CCDS9850

Canonical transcript exons

ENST00000644823 — 7 exons

Exon	Start	End
ENSE00000392836	76482016	76482126
ENSE00000808459	76482598	76482759
ENSE00001193983	76491447	76491716
ENSE00002022824	76376137	76376451
ENSE00003556992	76439341	76439750
ENSE00003618979	76462545	76462661
ENSE00003821703	76498214	76501837

Expression profiles

Bgee: expression breadth ubiquitous, 131 present calls, max score 81.25.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4875 / max 133.8316, expressed in 100 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140719	0.3023	45
140717	0.0571	23
140718	0.0534	28
140723	0.0251	9
140720	0.0241	8
140722	0.0166	7
140721	0.0090	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
metanephros cortex	UBERON:0010533	81.25	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.83	gold quality
adult mammalian kidney	UBERON:0000082	78.37	gold quality
hindlimb stylopod muscle	UBERON:0004252	77.96	gold quality
apex of heart	UBERON:0002098	77.55	gold quality
gastrocnemius	UBERON:0001388	75.10	gold quality
muscle of leg	UBERON:0001383	74.72	gold quality
metanephros	UBERON:0000081	74.19	gold quality
heart left ventricle	UBERON:0002084	74.08	gold quality
renal medulla	UBERON:0000362	73.61	gold quality
cardiac ventricle	UBERON:0002082	73.31	gold quality
kidney	UBERON:0002113	71.43	gold quality
body of stomach	UBERON:0001161	70.50	gold quality
right atrium auricular region	UBERON:0006631	70.47	gold quality
cardiac atrium	UBERON:0002081	69.70	gold quality
heart	UBERON:0000948	68.16	gold quality
cortex of kidney	UBERON:0001225	67.60	gold quality
stomach	UBERON:0000945	66.26	gold quality
parotid gland	UBERON:0001831	65.87	gold quality
skeletal muscle tissue	UBERON:0001134	65.04	gold quality
secondary oocyte	CL:0000655	64.47	gold quality
muscle tissue	UBERON:0002385	63.11	gold quality
pigmented layer of retina	UBERON:0001782	62.22	silver quality
fundus of stomach	UBERON:0001160	62.16	gold quality
biceps brachii	UBERON:0001507	61.81	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	61.63	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	59.79	gold quality
endothelial cell	CL:0000115	59.78	gold quality
ganglionic eminence	UBERON:0004023	59.75	gold quality
cortical plate	UBERON:0005343	59.67	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	1074.05
E-CURD-119	yes	892.18
E-ANND-3	yes	3.91

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

12 targets.

Target	Regulation
BCAS2	Unknown
BRCA2	Unknown
CDH1
CDKN1A	Unknown
ESRRB
FST
NANOG	Activation
NR0B1	Activation
NRIP1
OTX2
POU5F1	Activation
THRA

JASPAR motifs

Motif	Name	Family
MA0141.3	ESRRB	Steroid hormone receptors (NR3)
MA0141.4	ESRRB	Steroid hormone receptors (NR3)

JASPAR matrix evidence (PMIDs): PMID:18555785

Upstream regulators (CollecTRI, top): ESRRB, NANOG, NR0B1, PRDM4, TCF3

Literature-anchored findings (GeneRIF, showing 38)

• ERRs, which are coexpressed with ERs in prostatic cells, could regulate cell growth and modulate ER-mediated pathways via interference on ERalpha transcription in prostatic cells. (PMID:15598686)
• Short-form hERRbeta lacks an F domain and is the matched homolog of mouse and rat ERRbeta proteins in human. However, hERRbeta2-Delta10 and the previously reported hERRbeta2 isoforms are primate specific. (PMID:16332939)
• ERRbeta plays a repressor role in the Nrf2-ARE pathway (PMID:17920186)
• ERRbeta performs a tumor suppressing function in prostate cancer cells. (PMID:18071305)
• Data indicate that ESRRB is essential for inner-ear development and function and a frame shift mutation in ESRRB results in non-syndromic hearing impairment. (PMID:18179891)
• Sequence analysis of the ESRRB gene in the affected individuals of the original DFNB35 family and in three other DFNB35-linked consanguineous families from Pakistan revealed four missense mutations. (PMID:18179891)
• Receptor estrogen-related receptors alpha, beta and gamma physically interact with HIF and stimulate HIF-induced transcription in tumor cells cultured under hypoxia. (PMID:18509053)
• ERRbeta protein was localized to cell nuclei within multiple endometrial cell types including the glands, stroma, endothelium and immune cells, including uterine natural killer (uNK) cells and macrophages throughout normal menstrual cycle. (PMID:18775884)
• Esrrb coordinates with Nanog and Oct4 to activate the internal machinery of ES cells (PMID:18957414)
• Data show that variant isoforms of estrogen receptor related beta protein have differential effects on ER alpha-dependent gene expression, and possibly on endometrial cell function. (PMID:19755138)
• Parkin degrades ESRRA, ESRRB and ESRRG to limit the expression of MAOA and MAOB. (PMID:21177257)
• Data confirm the up-regulation of ER-beta as the principal receptor involved in the progression of human endometriosis. (PMID:21561608)
• A novel missense mutation in the ESRRB gene causes DFNB35 hearing loss in a Tunisian family. (PMID:21802533)
• This is the first report of DFNB35 mutations in the Czech Republic and it seems to be a rare cause of non-syndromic hearing loss. (PMID:22951369)
• ERRbeta signalling leads to BCAS2-mediated blockage of the G1/S transition and inhibition of the epithelial to mesenchymal transition through FST-mediated regulation of E-cadherin (PMID:24667650)
• study concludes ESRRB, a gene when mutated causes a form of hearing impairment, also contributes to dental decay likely by influencing the formation of an enamel surface more susceptible to demineralization under acidic conditions (PMID:25023176)
• The significant association and the presence of high-risk haplotypes identified in the ESRRB gene confirm the association of variants in ESRRB and rotator cuff disease. (PMID:25219474)
• ERRbeta has a role in estrogen-dependent cellular function including cancer cell proliferation (PMID:25805499)
• The rs1676303 TT (P=0.02) and rs6574293 GG (P=0.04) genotypes of ESRRB were associated with RCD and TMD, respectively. (PMID:26584852)
• analysis of Esrrb target genes indicates Esrrb may be an important factor in regulating cell proliferation (PMID:26627478)
• SNP (rs61742642; C to T, P386S) in the ligand-binding domain of human estrogen-related receptor beta is associated with audiometric temporary threshold shift. (PMID:27399974)
• ESRRbeta is mislocalized in human myocardium samples with idiopathic dilated cardiomyopathy, suggesting a possible role for ESRRbeta in the pathogenesis of idiopathic dilated cardiomyopathy in humans (PMID:28130335)
• the calcium level was associated with genetic variations in AMELX, AMNB and ESRRB. AMELX and AMNB are involved in enamel mineralization. Mutations in both these genes are responsible for the amelogenesis imperfecta phenotype (OMIN), which supports their link with enamel alterations as well as enamel mineralization. (PMID:28395292)
• Esrrb activity at crucial regulatory elements of the pluripotency network, coupled with its role as a mitotic bookmarking factor and the ability to reset cellular metabolism, might explain its potent functions in ensuring the stability of pluripotency and driving the late stages of reprogramming. (PMID:28834535)
• For the ESRRB (rs1676303) gene, an association was observed between the CC (cytosine/cytosine) genotype and the presence of articular TMDs associated with other chronic arthralgia (P = .02). (PMID:29175417)
• Study results indicate that ERRbeta is a negative regulator of cell cycle and a possible tumor suppressor in breast cancer. (PMID:29843638)
• The orphan nuclear receptor Esrrb plays a pioneering role in recruiting the core pluripotency factors Oct4, Sox2, and Nanog to inactive enhancers in closed chromatin during the reprogramming of epiblast stem cells. (PMID:29910149)
• EZH2 as a relevant coregulator for estrogen-related receptors alpha, beta and gamma in breast carcinoma. (PMID:29940916)
• rs12437118 associated with tuberculosis risk in Han Chinese (PMID:30287856)
• ESRRB regulates glucocorticoid gene expression in mice and patients with acute lymphoblastic leukemia. (PMID:32658986)
• Structural Insights into the Specificity of Ligand Binding and Coactivator Assembly by Estrogen-Related Receptor beta. (PMID:32795533)
• Estrogen-related receptors: novel potential regulators of osteoarthritis pathogenesis. (PMID:33446092)
• Expression of estrogen-related receptors in ovarian cancer and impact on survival. (PMID:34089362)
• A novel missense variant in ESRRB gene causing autosomal recessive non-syndromic hearing loss: in silico analysis of a case. (PMID:35101039)
• Long Noncoding RNA ACTA2-AS1 Inhibits Cell Growth and Facilitates Apoptosis in Gastric Cancer by Binding with miR-6720-5p to Regulate ESRRB. (PMID:37222961)
• ESRRB Inhibits the TGFbeta Signaling Pathway to Drive Cell Proliferation in Cervical Cancer. (PMID:37350664)
• SIRT1 mediates breast cancer development and tumorigenesis controlled by estrogen-related receptor beta. (PMID:38421553)
• Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35). (PMID:39261511)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	esrrb	ENSDARG00000100847
mus_musculus	Esrrb	ENSMUSG00000021255
rattus_norvegicus	Esrrb	ENSRNOG00000010259
drosophila_melanogaster	ERR	FBGN0035849

Paralogs (8): PGR (ENSG00000082175), ESR1 (ENSG00000091831), NR3C1 (ENSG00000113580), ESR2 (ENSG00000140009), NR3C2 (ENSG00000151623), AR (ENSG00000169083), ESRRA (ENSG00000173153), ESRRG (ENSG00000196482)

Protein

Protein identifiers

Steroid hormone receptor ERR2 — O95718 (reviewed: O95718)

Alternative names: ERR beta-2, Estrogen receptor-like 2, Estrogen-related receptor beta, Nuclear receptor subfamily 3 group B member 2

All UniProt accessions (4): A0A2R8Y491, A0A2R8Y509, E7EWD9, O95718

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds a canonical ESRRB recognition (ERRE) sequence 5’TCAAGGTCA-3’ localized on promoter and enhancer of targets genes regulating their expression or their transcription activity. Plays a role, in a LIF-independent manner, in maintainance of self-renewal and pluripotency of embryonic and trophoblast stem cells through different signaling pathways including FGF signaling pathway and Wnt signaling pathways. Involved in morula development (2-16 cells embryos) by acting as a regulator at the 8-cell stage. Upon FGF signaling pathway activation, interacts with KDM1A by directly binding to enhancer site of ELF5 and EOMES and activating their transcription leading to self-renewal of trophoblast stem cells. Also regulates expression of multiple rod-specific genes and is required for survival of this cell type. Plays a role as transcription factor activator of GATA6, NR0B1, POU5F1 and PERM1. Plays a role as transcription factor repressor of NFE2L2 transcriptional activity and ESR1 transcriptional activity. During mitosis remains bound to a subset of interphase target genes, including pluripotency regulators, through the canonical ESRRB recognition (ERRE) sequence, leading to their transcriptional activation in early G1 phase. Can coassemble on structured DNA elements with other transcription factors like SOX2, POU5F1, KDM1A and NCOA3 to trigger ESRRB-dependent gene activation. This mechanism, in the case of SOX2 corecruitment prevents the embryonic stem cells (ESCs) to epiblast stem cells (EpiSC) transition through positive regulation of NR0B1 that inhibits the EpiSC transcriptional program. Also plays a role inner ear development by controlling expression of ion channels and transporters and in early placentation. Transcription factor that binds a canonical ESRRB recognition (ERRE) sequence 5’TCAAGGTCA-3’ localized on promoter and enhancer of targets genes regulating their expression or their transcription activity. Positively regulates ESR1 transcriptional activity upon E2 stimulation.

Subunit / interactions. Binds DNA as a monomer. Interacts with NR0B1; represses ESRRB activity at the GATA6 promoter. Interacts with NANOG; reciprocally modulates their transcriptional activities and activates POU5F1 expression. Interacts with NCOA3; 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 KDM1A; co-occupes the core set of ESRRB targets including ELF5 and EOMES. Interacts with the multiprotein complex Integrator, at least composed of INTS1, INTS2, INTS3, INTS4, INTS5, INTS6, INTS7, INTS8, INTS9/RC74, INTS10, INTS11/CPSF3L and INTS12; ESRRB is probably not a core component of the integrator complex and associates to integrator via its interaction with INTS1 and INTS9; attracts the transcriptional machinery. Interacts with JARID2. Interacts with POU5F1; recruits ESRRB near the POU5F1-SOX2 element in the NANOG proximal promoter leading to activation of NANOG expression; the interaction is DNA independent. Interacts with NFE2L2; represses NFE2L2 transcriptional activity. Isoform 1 interacts with ESR1.

Subcellular location. Nucleus. Cytoplasm. Chromosome.

Post-translational modifications. Acetylated by PCAF/KAT2 (in vitro).

Disease relevance. Deafness, autosomal recessive, 35 (DFNB35) [MIM:608565] A form of non-syndromic deafness characterized by non-progressive, prelingual hearing loss. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Primate-specific splicing isoform. Primate-specific splicing isoform.

Similarity. Belongs to the nuclear hormone receptor family. NR3 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
O95718-3	3, ERRbeta-short-form	yes
O95718-1	1, ERRbeta2-delta10
O95718-2	2, ERRbeta2

RefSeq proteins (3): NP_001366109, NP_001397967, NP_004443 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR024178	Est_rcpt/est-rel_rcp	Family
IPR027289	Oest-rel_rcp	Family
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR050200	Nuclear_hormone_rcpt_NR3	Family

Pfam: PF00104, PF00105

UniProt features (42 total): helix 15, sequence variant 6, strand 4, region of interest 3, splice variant 2, sequence conflict 2, turn 2, zinc finger region 2, chain 1, domain 1, mutagenesis site 1, DNA-binding region 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6LIT	X-RAY DIFFRACTION	2
6LN4	X-RAY DIFFRACTION	2.61
1LO1	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95718-F1	79.14	0.62

Functional residue map

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

Catalytic / active sites (1): 185 (important for stabilizing dna-binding)

Mutagenesis-validated functional residues (1):

Position	Phenotype
185	6-fold decrease in dna-binding affinity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway

MSigDB gene sets: 160 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, GAANYNYGACNY_UNKNOWN, RORA1_01, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_NEGATIVE_REGULATION_OF_STEM_CELL_DIFFERENTIATION, TGACCTY_ERR1_Q2, RIZKI_TUMOR_INVASIVENESS_3D_DN, AAAYRNCTG_UNKNOWN, CAGCTG_AP4_Q5, GOBP_STEM_CELL_DIVISION, GOBP_EMBRYONIC_PLACENTA_DEVELOPMENT, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_EAR_DEVELOPMENT, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT

GO Biological Process (17): regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), cell population proliferation (GO:0008283), stem cell division (GO:0017145), stem cell population maintenance (GO:0019827), somatic stem cell population maintenance (GO:0035019), cell dedifferentiation (GO:0043697), photoreceptor cell maintenance (GO:0045494), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), inner ear development (GO:0048839), morula formation (GO:0140001), positive regulation of stem cell population maintenance (GO:1902459), regulation of stem cell division (GO:2000035), negative regulation of stem cell differentiation (GO:2000737), nuclear receptor-mediated steroid hormone signaling pathway (GO:0030518), intracellular receptor signaling pathway (GO:0030522)

GO Molecular Function (18): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), RNA polymerase II complex binding (GO:0000993), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), nuclear steroid receptor activity (GO:0003707), nuclear receptor activity (GO:0004879), steroid binding (GO:0005496), zinc ion binding (GO:0008270), estrogen response element binding (GO:0034056), sequence-specific DNA binding (GO:0043565), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), lipid binding (GO:0008289), metal ion binding (GO:0046872)

GO Cellular Component (8): chromatin (GO:0000785), condensed chromosome (GO:0000793), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), chromosome (GO:0005694), integrator complex (GO:0032039)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
DNA-templated transcription	2
transcription by RNA polymerase II	2
multicellular organismal process	2
stem cell population maintenance	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
binding	2
chromosome	2
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cellular process	1
cell division	1
maintenance of cell number	1
dedifferentiation	1
cellular developmental process	1
retina homeostasis	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
ear development	1
anatomical structure development	1
anatomical structure formation involved in morphogenesis	1
positive regulation of developmental process	1
positive regulation of multicellular organismal process	1
regulation of stem cell population maintenance	1
stem cell division	1
regulation of cell division	1
negative regulation of cell differentiation	1
stem cell differentiation	1
regulation of stem cell differentiation	1
steroid hormone receptor signaling pathway	1
nuclear receptor-mediated signaling pathway	1
intracellular signal transduction	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
RNA polymerase core enzyme binding	1

Protein interactions and networks

STRING

1838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ESRRB	SALL4	Q9UJQ4	919
ESRRB	NANOG	Q9H9S0	909
ESRRB	POU5F1	P31359	886
ESRRB	SOX2	P48431	849
ESRRB	SLC7A1	P30825	842
ESRRB	KLF5	Q13887	841
ESRRB	EGFR	P00533	840
ESRRB	TBX3	O15119	822
ESRRB	NR0B1	P51843	813
ESRRB	KLF4	P78338	793
ESRRB	TFCP2L1	Q9NZI6	791
ESRRB	CDX2	Q99626	764
ESRRB	EOMES	O95936	738
ESRRB	PRDM14	Q9GZV8	734
ESRRB	ZFP42	Q96MM3	724

IntAct

21 interactions, top by confidence:

A	B	Type	Score
	ESRRB	psi-mi:“MI:0915”(physical association)	0.370
CCL8	ESRRB	psi-mi:“MI:0915”(physical association)	0.370
IFNA5	ESRRB	psi-mi:“MI:0915”(physical association)	0.370
IL12B	ESRRB	psi-mi:“MI:0915”(physical association)	0.370
IL17A	ESRRB	psi-mi:“MI:0915”(physical association)	0.370
IL31	ESRRB	psi-mi:“MI:0915”(physical association)	0.370
TNFSF14	ESRRB	psi-mi:“MI:0915”(physical association)	0.370
ESRRG	DDX3Y	psi-mi:“MI:0914”(association)	0.350
OR11G2	MLNR	psi-mi:“MI:0914”(association)	0.350
ESRRB	ESRRA	psi-mi:“MI:0914”(association)	0.350
FHIP1B	MED19	psi-mi:“MI:2364”(proximity)	0.270
FHIP2A	MED19	psi-mi:“MI:2364”(proximity)	0.270
	ESRRB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (106): ESRRB (Affinity Capture-Western), ESRRB (Affinity Capture-Western), ESRRB (Two-hybrid), ESRRB (Two-hybrid), YWHAQ (Affinity Capture-MS), PPP2R1A (Affinity Capture-MS), SLC3A2 (Affinity Capture-MS), ACSL3 (Affinity Capture-MS), SLC25A5 (Affinity Capture-MS), SLC25A6 (Affinity Capture-MS), ANXA2 (Affinity Capture-MS), ATP1A1 (Affinity Capture-MS), ATP2A2 (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), ATAD3A (Affinity Capture-MS)

ESM2 similar proteins: A0P8Z4, O00482, O35507, O42101, O76202, O95718, P03372, P06211, P11475, P19785, P22449, P28701, P28705, P35396, P35398, P37234, P41235, P45448, P48443, P49698, P49867, P49884, P51128, P51129, P51448, P54779, P57783, P70033, Q03181, Q06726, Q0GFF6, Q0VC20, Q0ZAQ8, Q15406, Q29040, Q4V8R7, Q505F1, Q5BJR8, Q5REL6, Q61539

Diamond homologs: A2T928, A2T929, G5ECR9, O00482, O08580, O09017, O09018, O42101, O44960, O45666, O76202, O95718, P10276, P10588, P10589, P10826, P11416, P11474, P11475, P13631, P16375, P16376, P18514, P18516, P18911, P19793, P20153, P22448, P22449, P22605, P24468, P28699, P28700, P28701, P28702, P28704, P28705, P41235, P43135, P43136

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ESRRB	down-regulates	NR0B1

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	14
Uncertain significance	158
Likely benign	84
Benign	27

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1174538	NM_001379180.1(ESRRB):c.562G>A (p.Gly188Arg)	Pathogenic
2137608	NM_001379180.1(ESRRB):c.498C>A (p.Cys166Ter)	Pathogenic
3606196	NM_001379180.1(ESRRB):c.933C>A (p.Tyr311Ter)	Pathogenic
3775555	NM_001379180.1(ESRRB):c.661C>T (p.Gln221Ter)	Pathogenic
402254	NM_001379180.1(ESRRB):c.608G>A (p.Arg203His)	Pathogenic
402255	NM_001379180.1(ESRRB):c.850G>A (p.Gly284Ser)	Pathogenic
4689316	NM_001379180.1(ESRRB):c.1335_1336del (p.Phe446fs)	Pathogenic
4731694	NM_001379180.1(ESRRB):c.752del (p.Pro251fs)	Pathogenic
7498	NM_001379180.1(ESRRB):c.1081_1087dup (p.Val363fs)	Pathogenic
7499	NM_001379180.1(ESRRB):c.392C>T (p.Ala131Val)	Pathogenic
7500	NM_001379180.1(ESRRB):c.1087G>T (p.Val363Leu)	Pathogenic
1028247	NM_001379180.1(ESRRB):c.*1451C>G	Likely pathogenic
163415	NM_004452.3(ESRRB):c.(?1501)(1527_?)del (p.?)	Likely pathogenic
163423	NM_001379180.1(ESRRB):c.1224G>A (p.Trp408Ter)	Likely pathogenic
178970	NM_001379180.1(ESRRB):c.1268_1272del (p.Thr423fs)	Likely pathogenic
228259	NM_001379180.1(ESRRB):c.1088_1089del (p.Val363fs)	Likely pathogenic
2498597	NM_001379180.1(ESRRB):c.738T>G (p.Tyr246Ter)	Likely pathogenic
2719517	NM_001379180.1(ESRRB):c.688+1G>A	Likely pathogenic
3045120	NM_001379180.1(ESRRB):c.851-2A>T	Likely pathogenic
3601086	NM_001379180.1(ESRRB):c.834G>C (p.Trp278Cys)	Likely pathogenic
3606848	NM_001379180.1(ESRRB):c.577+2T>C	Likely pathogenic
3771628	NM_001379180.1(ESRRB):c.*1451C>A	Likely pathogenic
4532194	NM_001379180.1(ESRRB):c.976T>C (p.Tyr326His)	Likely pathogenic
505350	NM_001379180.1(ESRRB):c.1011dup (p.Leu338fs)	Likely pathogenic
517379	NM_001379180.1(ESRRB):c.808C>T (p.Arg270Ter)	Likely pathogenic

SpliceAI

1143 predictions. Top by Δscore:

Variant	Effect	Δscore
14:76439336:CACA:C	acceptor_loss	1.0000
14:76439338:CAGGC:C	acceptor_loss	1.0000
14:76439339:A:AG	acceptor_gain	1.0000
14:76439340:G:GG	acceptor_gain	1.0000
14:76439340:G:GT	acceptor_loss	1.0000
14:76439340:GGCT:G	acceptor_gain	1.0000
14:76439748:AAGGT:A	donor_loss	1.0000
14:76439751:G:GA	donor_loss	1.0000
14:76439752:T:G	donor_loss	1.0000
14:76462543:A:AG	acceptor_gain	1.0000
14:76462544:G:GG	acceptor_gain	1.0000
14:76462657:GGAAG:G	donor_gain	1.0000
14:76462658:GAAGG:G	donor_gain	1.0000
14:76462659:A:T	donor_gain	1.0000
14:76462659:AAGGT:A	donor_loss	1.0000
14:76462662:G:T	donor_loss	1.0000
14:76462663:T:G	donor_loss	1.0000
14:76482010:CAATA:C	acceptor_loss	1.0000
14:76482012:ATAGG:A	acceptor_loss	1.0000
14:76482013:TAGG:T	acceptor_loss	1.0000
14:76482014:A:T	acceptor_loss	1.0000
14:76482015:G:GA	acceptor_loss	1.0000
14:76482122:GCCAT:G	donor_gain	1.0000
14:76482123:CCAT:C	donor_gain	1.0000
14:76482127:G:GG	donor_gain	1.0000
14:76482586:T:TA	acceptor_gain	1.0000
14:76482595:CA:C	acceptor_loss	1.0000
14:76482596:A:AG	acceptor_gain	1.0000
14:76482596:AGT:A	acceptor_gain	1.0000
14:76482597:G:GC	acceptor_gain	1.0000

AlphaMissense

2959 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000253 (14:76339727 C>G), RS1000019183 (14:76416508 C>T), RS1000097611 (14:76476550 G>C), RS1000104613 (14:76335711 G>A,C,T), RS1000108365 (14:76435787 C>T), RS1000133160 (14:76461940 G>A), RS1000137471 (14:76331874 G>A,T), RS1000140147 (14:76397006 C>G,T), RS1000153517 (14:76318905 A>G), RS1000180091 (14:76459087 T>C,G), RS1000183972 (14:76334044 T>A), RS1000185264 (14:76496205 G>A,C), RS1000190776 (14:76499466 C>A,G), RS1000199408 (14:76399387 A>G), RS1000226093 (14:76412838 A>G)

Disease associations

OMIM: gene MIM:602167 | disease phenotypes: MIM:608565, MIM:615582, MIM:220290, MIM:607197

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 35	Definitive	Autosomal recessive
nonsyndromic genetic hearing loss	Definitive	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AR

Mondo (6): autosomal recessive nonsyndromic hearing loss 35 (MONDO:0012060), hearing loss disorder (MONDO:0005365), Rienhoff syndrome (MONDO:0014262), premature menopause (MONDO:0001119), hearing loss, autosomal recessive (MONDO:0019588), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (3): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare genetic deafness (Orphanet:96210), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000504	Abnormality of vision
HP:0003577	Congenital onset
HP:0031703	Abnormal ear morphology

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002664_3	Maximal oxygen uptake response	7.000000e-06
GCST006619_1	Tuberculosis	2.000000e-11
GCST008865_3	Sphingomyelin 24:0 levels	6.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004887	maximal oxygen uptake measurement
EFO:0010118	sphingomyelin measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
C564609	Deafness, Autosomal Recessive (supp.)
C563908	Deafness, Autosomal Recessive 35 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3751 (SINGLE PROTEIN), CHEMBL4523724 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 167,292 (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
CHEMBL135	ESTRADIOL	4	123,080
CHEMBL44	GENISTEIN	2	44,212

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: nhr — 3B. Estrogen-related receptors

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
diethylstilbestrol	Antagonist	5.3	pIC50

Binding affinities (BindingDB)

12 measured of 12 human assays (12 total across all organisms); most potent 12 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-1-one	KI	0.48 nM	US-9623021: Nuclear receptor binding agents
6,8-dihydroxy-2-(4-hydroxyphenyl)-4-[(E)-prop-1-enyl]isoquinolin-1-one	KI	1.66 nM	US-9623021: Nuclear receptor binding agents
4-bromo-6,8-dihydroxy-2-(4-hydroxyphenyl)isoquinolin-1-one	KI	3 nM	US-9623021: Nuclear receptor binding agents
6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-1-one	KI	3.03 nM	US-9623021: Nuclear receptor binding agents
4-ethenyl-2-(3-fluoro-4-hydroxyphenyl)-6,8-dihydroxyisoquinolin-1-one	KI	3.96 nM	US-9623021: Nuclear receptor binding agents
4-bromo-6-hydroxy-2-(4-hydroxyphenyl)-1-oxoisoquinoline-8-carbonitrile	KI	6 nM	US-9623021: Nuclear receptor binding agents
4-bromo-2-(3-fluoro-4-hydroxyphenyl)-6,8-dihydroxyisoquinolin-1-one	KI	40 nM	US-9604931: Nuclear receptor binding agents
4-bromo-6-methoxy-2-(4-methoxyphenyl)-1-oxoisoquinoline-8-carbonitrile	KI	46 nM	US-9623021: Nuclear receptor binding agents
4-bromo-6-hydroxy-2-(4-hydroxyphenyl)isoquinolin-1-one	KI	49 nM	US-9623021: Nuclear receptor binding agents
6,8-dihydroxy-2-(4-hydroxyphenyl)-1-oxoisoquinoline-4-carbonitrile	KI	94 nM	US-9604931: Nuclear receptor binding agents
6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-1-one	KI	252 nM	US-9623021: Nuclear receptor binding agents
6-hydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-1-one	KI	2100 nM	US-9604931: Nuclear receptor binding agents

ChEMBL bioactivities

115 potent at pChembl≥5 of 115 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.49	IC50	3.2	nM	ESTRADIOL
8.34	EC50	4.6	nM	ESTRADIOL
8.06	IC50	8.7	nM	ESTRADIOL
8.00	IC50	10	nM	CHEMBL4071073
7.72	IC50	19.1	nM	CHEMBL2326072
7.70	EC50	20	nM	CHEMBL4206963
7.51	EC50	31	nM	CHEMBL4217033
7.38	IC50	41.2	nM	CHEMBL2326068
7.35	EC50	45	nM	CHEMBL4211016
7.30	IC50	50	nM	CHEMBL4100590
7.25	IC50	56	nM	CHEMBL250097
7.16	IC50	70	nM	CHEMBL4596092
7.06	IC50	88	nM	CHEMBL402491
7.05	EC50	90	nM	CHEMBL4204689
7.01	IC50	98	nM	CHEMBL402492
6.95	IC50	111.9	nM	CHEMBL2326070
6.92	IC50	120.7	nM	CHEMBL2326073
6.82	IC50	150.6	nM	CHEMBL2326069
6.73	IC50	185	nM	CHEMBL2326076
6.68	IC50	210	nM	CHEMBL4092854
6.67	IC50	212	nM	CHEMBL198411
6.67	IC50	213	nM	CHEMBL372783
6.52	IC50	300	nM	CHEMBL4085105
6.48	IC50	331.1	nM	CHEMBL2326074
6.46	IC50	350	nM	CHEMBL4084142
6.40	IC50	395	nM	GENISTEIN
6.36	IC50	436.4	nM	CHEMBL2326075
6.34	IC50	455	nM	CHEMBL197667
6.30	IC50	504	nM	CHEMBL198089
6.30	IC50	504	nM	CHEMBL250302
6.28	IC50	526	nM	CHEMBL250300
6.26	IC50	550	nM	CHEMBL4064664
6.26	IC50	549	nM	CHEMBL250507
6.25	IC50	565.9	nM	CHEMBL2326071
6.22	IC50	600	nM	CHEMBL4065193
6.21	IC50	624	nM	CHEMBL250301
6.20	EC50	630	nM	CHEMBL4205664
6.20	IC50	634	nM	CHEMBL198679
6.19	IC50	650	nM	CHEMBL2137046
6.19	IC50	641	nM	CHEMBL402493
6.14	IC50	722	nM	CHEMBL3961676
6.12	IC50	750	nM	CHEMBL4073790
6.11	IC50	774	nM	CHEMBL4795846
6.09	IC50	820	nM	CHEMBL398815
6.07	IC50	861	nM	CHEMBL4437929
6.07	IC50	861	nM	CHEMBL4598385
6.05	IC50	886	nM	CHEMBL2137046
6.01	IC50	980	nM	CHEMBL4585424
6.01	IC50	980	nM	CHEMBL4595194
6.00	IC50	990	nM	CHEMBL4541589

PubChem BioAssay actives

92 with measured affinity, of 174 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
Estradiol	307630: Inhibition of human ERbeta	ic50	0.0032	uM
[4-[(E)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-3-methyl-2-phenylbut-1-enyl]phenyl] acetate	1432443: Inverse agonist activity at GAL4-DNA binding domain-fused human ERRbeta ligand binding domain expressed in African green monkey CV1 cells assessed as decrease in receptor transcriptional activity after 45 hrs by luciferase reporter gene assay	ic50	0.0100	uM
(7R,8R,9S,13S,14S,17S)-13-methyl-7-[6-(4-pyrrol-1-ylphenyl)hex-5-ynyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol	728189: Displacement of [3H]E2 from human recombinant ERbeta receptor after overnight incubation by liquid scintillation counting analysis	ic50	0.0191	uM
N-[2-(4-tert-butylphenyl)ethyl]-4-hydroxy-2-methylbenzamide	1375003: Agonist activity at alphaHis-SUMO-tagged ERRbeta-LBD (unknown origin) assessed as decrease in RIP140 peptide recruitment by TR-FRET assay	ec50	0.0200	uM
N-[2-(4-tert-butylphenyl)ethyl]-2-chloro-4-hydroxybenzamide	1375003: Agonist activity at alphaHis-SUMO-tagged ERRbeta-LBD (unknown origin) assessed as decrease in RIP140 peptide recruitment by TR-FRET assay	ec50	0.0310	uM
(7R,8R,9S,13S,14S,17S)-7-[4-[1-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)triazol-4-yl]butyl]-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol	728189: Displacement of [3H]E2 from human recombinant ERbeta receptor after overnight incubation by liquid scintillation counting analysis	ic50	0.0412	uM
2-amino-N-[2-(4-tert-butylphenyl)ethyl]-4-hydroxybenzamide	1375003: Agonist activity at alphaHis-SUMO-tagged ERRbeta-LBD (unknown origin) assessed as decrease in RIP140 peptide recruitment by TR-FRET assay	ec50	0.0450	uM
methyl (Z)-5-[4-[2-(dimethylamino)ethoxy]phenyl]-5-(4-hydroxyphenyl)-2-methyl-4-phenylpent-4-enoate	1432443: Inverse agonist activity at GAL4-DNA binding domain-fused human ERRbeta ligand binding domain expressed in African green monkey CV1 cells assessed as decrease in receptor transcriptional activity after 45 hrs by luciferase reporter gene assay	ic50	0.0500	uM
7-bromo-6H-chromeno[4,3-b]quinoline-3,9-diol	307630: Inhibition of human ERbeta	ic50	0.0560	uM
7-chloro-6H-chromeno[4,3-b]quinoline-3,9-diol	307630: Inhibition of human ERbeta	ic50	0.0880	uM
N-[2-(4-tert-butylphenyl)ethyl]-4-hydroxybenzamide	1375003: Agonist activity at alphaHis-SUMO-tagged ERRbeta-LBD (unknown origin) assessed as decrease in RIP140 peptide recruitment by TR-FRET assay	ec50	0.0900	uM
3,9-dihydroxy-6H-chromeno[4,3-b]quinoline-7-carbonitrile	307630: Inhibition of human ERbeta	ic50	0.0980	uM
3-[4-[4-[(7R,8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-7-yl]butyl]triazol-1-yl]-7-hydroxychromen-2-one	728189: Displacement of [3H]E2 from human recombinant ERbeta receptor after overnight incubation by liquid scintillation counting analysis	ic50	0.1119	uM
(7R,8R,9S,13S,14S,17S)-13-methyl-7-(6-naphthalen-2-ylhex-5-ynyl)-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol	728189: Displacement of [3H]E2 from human recombinant ERbeta receptor after overnight incubation by liquid scintillation counting analysis	ic50	0.1207	uM
diethyl 2-[[4-[6-[(7R,8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-7-yl]hex-1-ynyl]phenyl]methyl]propanedioate	728189: Displacement of [3H]E2 from human recombinant ERbeta receptor after overnight incubation by liquid scintillation counting analysis	ic50	0.1506	uM
ethyl 3-[4-[6-[(7R,8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-7-yl]hex-1-ynyl]phenyl]-3-oxopropanoate	728189: Displacement of [3H]E2 from human recombinant ERbeta receptor after overnight incubation by liquid scintillation counting analysis	ic50	0.1850	uM
4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-3-methyl-2-phenylbut-1-enyl]phenol	1432443: Inverse agonist activity at GAL4-DNA binding domain-fused human ERRbeta ligand binding domain expressed in African green monkey CV1 cells assessed as decrease in receptor transcriptional activity after 45 hrs by luciferase reporter gene assay	ic50	0.2100	uM
4-bromo-2-(4-hydroxyphenyl)quinolin-6-ol	307630: Inhibition of human ERbeta	ic50	0.2120	uM
4-chloro-2-(4-hydroxyphenyl)quinolin-6-ol	307630: Inhibition of human ERbeta	ic50	0.2130	uM
methyl 5,5-bis(4-hydroxyphenyl)-2-methyl-4-phenylpent-4-enoate	1432443: Inverse agonist activity at GAL4-DNA binding domain-fused human ERRbeta ligand binding domain expressed in African green monkey CV1 cells assessed as decrease in receptor transcriptional activity after 45 hrs by luciferase reporter gene assay	ic50	0.3000	uM
(7R,8R,9S,13S,14S,17S)-13-methyl-7-[6-[4-(1,2-oxazol-5-yl)phenyl]hex-5-ynyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol	728189: Displacement of [3H]E2 from human recombinant ERbeta receptor after overnight incubation by liquid scintillation counting analysis	ic50	0.3311	uM
methyl (Z)-5-[4-[2-(dimethylamino)ethoxy]phenyl]-5-(4-hydroxyphenyl)-4-phenylpent-4-enoate	1432443: Inverse agonist activity at GAL4-DNA binding domain-fused human ERRbeta ligand binding domain expressed in African green monkey CV1 cells assessed as decrease in receptor transcriptional activity after 45 hrs by luciferase reporter gene assay	ic50	0.3500	uM
Genistein	307630: Inhibition of human ERbeta	ic50	0.3950	uM
tert-butyl 4-[4-[6-[(7R,8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-7-yl]hex-1-ynyl]phenyl]piperazine-1-carboxylate	728189: Displacement of [3H]E2 from human recombinant ERbeta receptor after overnight incubation by liquid scintillation counting analysis	ic50	0.4364	uM
6-hydroxy-2-(4-hydroxyphenyl)quinoline-4-carbonitrile	307630: Inhibition of human ERbeta	ic50	0.4550	uM
7-(3-chlorophenyl)-6H-chromeno[4,3-b]quinoline-3,9-diol	307630: Inhibition of human ERbeta	ic50	0.5040	uM
4-ethenyl-2-(4-hydroxyphenyl)quinolin-6-ol	307630: Inhibition of human ERbeta	ic50	0.5040	uM
7-ethenyl-6H-chromeno[4,3-b]quinoline-3,9-diol	307630: Inhibition of human ERbeta	ic50	0.5260	uM
7-(4-methoxyphenyl)-6H-chromeno[4,3-b]quinoline-3,9-diol	307630: Inhibition of human ERbeta	ic50	0.5490	uM
[4-[(E)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-5-hydroxy-4-methyl-2-phenylpent-1-enyl]phenyl] acetate	1432443: Inverse agonist activity at GAL4-DNA binding domain-fused human ERRbeta ligand binding domain expressed in African green monkey CV1 cells assessed as decrease in receptor transcriptional activity after 45 hrs by luciferase reporter gene assay	ic50	0.5500	uM
(7R,8R,9S,13S,14S,17S)-13-methyl-7-[6-[4-(piperidin-1-ylmethyl)phenyl]hex-5-ynyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol	728189: Displacement of [3H]E2 from human recombinant ERbeta receptor after overnight incubation by liquid scintillation counting analysis	ic50	0.5659	uM
methyl 5,5-bis(4-hydroxyphenyl)-4-phenylpent-4-enoate	1432443: Inverse agonist activity at GAL4-DNA binding domain-fused human ERRbeta ligand binding domain expressed in African green monkey CV1 cells assessed as decrease in receptor transcriptional activity after 45 hrs by luciferase reporter gene assay	ic50	0.6000	uM
7-ethynyl-6H-chromeno[4,3-b]quinoline-3,9-diol	307630: Inhibition of human ERbeta	ic50	0.6240	uM
N-[2-[4-(diethylamino)phenyl]ethyl]-4-hydroxybenzamide	1375003: Agonist activity at alphaHis-SUMO-tagged ERRbeta-LBD (unknown origin) assessed as decrease in RIP140 peptide recruitment by TR-FRET assay	ec50	0.6300	uM
4-ethyl-2-(4-hydroxyphenyl)quinolin-6-ol	307630: Inhibition of human ERbeta	ic50	0.6340	uM
7-ethyl-6H-chromeno[4,3-b]quinoline-3,9-diol	307630: Inhibition of human ERbeta	ic50	0.6410	uM
4-[1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol	1432443: Inverse agonist activity at GAL4-DNA binding domain-fused human ERRbeta ligand binding domain expressed in African green monkey CV1 cells assessed as decrease in receptor transcriptional activity after 45 hrs by luciferase reporter gene assay	ic50	0.6500	uM
4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-5-fluoro-2-phenylpent-1-enyl]phenol;hydrochloride	1317929: Inhibition of fluorescien-conjugated coactivator PGC1a binding to ERRbeta (unknown origin) after 1 hr by TR-FRET assay	ic50	0.7220	uM
4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-4-methyl-2-phenylpent-1-enyl]phenol	1432443: Inverse agonist activity at GAL4-DNA binding domain-fused human ERRbeta ligand binding domain expressed in African green monkey CV1 cells assessed as decrease in receptor transcriptional activity after 45 hrs by luciferase reporter gene assay	ic50	0.7500	uM
4-[(E)-1-[4-(1-cyclopropylpiperidin-4-yl)phenyl]-5-fluoro-2-phenylpent-1-enyl]phenol;hydrochloride	1704116: Binding affinity to ERRbeta (unknown origin) by TR-FRET assay	ic50	0.7740	uM
7-(3-methoxyphenyl)-6H-chromeno[4,3-b]quinoline-3,9-diol	307630: Inhibition of human ERbeta	ic50	0.8200	uM
(Z)-5-(4-methylphenyl)-4-phenyl-5-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-4-en-1-ol;dihydrochloride	1614395: Binding affinity to ERRbeta (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.8610	uM
(E)-5-(4-bromophenyl)-4-phenyl-5-(4-piperazin-1-ylphenyl)pent-4-en-1-ol;dihydrochloride	1614395: Binding affinity to ERRbeta (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.9800	uM
(E)-5-(4-bromophenyl)-4-phenyl-5-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-4-en-1-ol;dihydrochloride	1614395: Binding affinity to ERRbeta (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.9900	uM
4-(3,9-dihydroxy-6H-chromeno[4,3-b]quinolin-7-yl)benzonitrile	307630: Inhibition of human ERbeta	ic50	1.0170	uM
(Z)-5-(4-methylphenyl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-4-phenylpent-4-en-1-ol;dihydrochloride	1614395: Binding affinity to ERRbeta (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	1.0170	uM
(Z)-5-[4-(4-ethylpiperazin-1-yl)phenyl]-5-(4-methylphenyl)-4-phenylpent-4-en-1-ol;dihydrochloride	1614395: Binding affinity to ERRbeta (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	1.0450	uM
[4-[(E)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-5-hydroxy-2-phenylpent-1-enyl]phenyl] acetate	1432443: Inverse agonist activity at GAL4-DNA binding domain-fused human ERRbeta ligand binding domain expressed in African green monkey CV1 cells assessed as decrease in receptor transcriptional activity after 45 hrs by luciferase reporter gene assay	ic50	1.1000	uM
3-(3,9-dihydroxy-6H-chromeno[4,3-b]quinolin-7-yl)benzonitrile	307630: Inhibition of human ERbeta	ic50	1.1300	uM
4-[(E)-1-[4-(azetidin-3-yl)phenyl]-5-fluoro-2-phenylpent-1-enyl]phenol;hydrochloride	1704116: Binding affinity to ERRbeta (unknown origin) by TR-FRET assay	ic50	1.3000	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	2
fluorene-9-bisphenol	increases expression	1
biochanin A	affects binding, increases activity, increases reaction	1
daidzein	affects binding, increases activity, increases reaction	1
bisphenol A	affects cotreatment, decreases methylation, increases methylation	1
ethyl-p-hydroxybenzoate	decreases expression	1
butylbenzyl phthalate	increases expression	1
flavone	affects binding, increases activity	1
abrine	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Troglitazone	increases expression	1
Acetaminophen	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Diethylstilbestrol	affects binding, decreases activity, decreases reaction, increases expression	1
Isoflavones	affects binding, increases activity	1
Lead	affects methylation	1
Plant Extracts	decreases expression	1
Rotenone	decreases expression	1
Aflatoxin B1	increases methylation	1
Genistein	affects binding, increases activity, increases reaction	1

ChEMBL screening assays

27 unique, capped per target: 19 binding, 8 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1679772	Functional	Agonist activity at ZFP-fused ERRbeta LBD expressed in HEK293 cells by TR-FRET assay	Identification of diaryl ether-based ligands for estrogen-related receptor α as potential antidiabetic agents. — J Med Chem
CHEMBL1961858	Binding	Effect on ERR2(NR3B2) dependent reporter activity in HEK293 cells at 20 uM	Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. — Nature

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1L3	SEES3-1V human ESRRB, clone1	Embryonic stem cell	Male
CVCL_A1L4	SEES3-1V human ESRRB, clone2	Embryonic stem cell	Male
CVCL_A1L5	SEES3-1V human ESRRB, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound