ESRRA

Summary

ESRRA (estrogen related receptor alpha, HGNC:3471) is a protein-coding gene on chromosome 11q13.1, encoding Steroid hormone receptor ERR1 (P11474). Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5’-TNAAGGTCA-3’. It is a selective cancer dependency (DepMap: 13.8% of cell lines).

The protein encoded by this gene is a nuclear receptor that is most closely related to the estrogen receptor. This protein acts as a site-specific transcription factor and interacts with members of the PGC-1 family of transcription cofactors to regulate the expression of most genes involved in cellular energy production as well as in the process of mitochondrial biogenesis. A processed pseudogene of ESRRA is located on chromosome 13q12.1.

Source: NCBI Gene 2101 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 59 total
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 13.8% of screened cell lines
• Transcription factor: yes — 58 downstream targets (CollecTRI)
• MANE Select transcript: NM_004451

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3471
Approved symbol	ESRRA
Name	estrogen related receptor alpha
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	ERR1, ERRalpha, NR3B1, ERRa
Ensembl gene	ENSG00000173153
Ensembl biotype	protein_coding
OMIM	601998
Entrez	2101

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 33 protein_coding, 1 retained_intron

ENST00000000442, ENST00000405666, ENST00000406310, ENST00000467987, ENST00000468670, ENST00000539594, ENST00000545035, ENST00000677967, ENST00000904903, ENST00000904904, ENST00000904905, ENST00000904906, ENST00000904907, ENST00000904908, ENST00000904909, ENST00000904910, ENST00000904911, ENST00000904912, ENST00000926785, ENST00000926786, ENST00000926787, ENST00000926788, ENST00000926789, ENST00000926790, ENST00000926791, ENST00000965463, ENST00000965464, ENST00000965465, ENST00000965467, ENST00000965468, ENST00000965469, ENST00000965470, ENST00000965471, ENST00000965472

RefSeq mRNA: 3 — MANE Select: NM_004451 NM_001282450, NM_001282451, NM_004451

CCDS: CCDS41667, CCDS60830

Canonical transcript exons

ENST00000000442 — 7 exons

Exon	Start	End
ENSE00000727249	64315001	64315270
ENSE00001195335	64314741	64314911
ENSE00001195360	64307168	64307504
ENSE00001564429	64315707	64316743
ENSE00001884684	64305524	64305736
ENSE00003471121	64314239	64314367
ENSE00003589560	64313951	64314067

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 98.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.5815 / max 208.3501, expressed in 1814 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114947	14.6644	1796
114945	6.7796	1771
114946	1.6191	1080
114948	0.3171	117
114949	0.2013	99

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.32	gold quality
mucosa of transverse colon	UBERON:0004991	97.44	gold quality
gastrocnemius	UBERON:0001388	97.26	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.04	gold quality
right atrium auricular region	UBERON:0006631	96.69	gold quality
heart left ventricle	UBERON:0002084	96.68	gold quality
cardiac ventricle	UBERON:0002082	96.43	gold quality
muscle of leg	UBERON:0001383	96.17	gold quality
metanephros cortex	UBERON:0010533	95.99	gold quality
cardiac atrium	UBERON:0002081	95.65	gold quality
transverse colon	UBERON:0001157	95.40	gold quality
right lobe of liver	UBERON:0001114	94.69	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.67	gold quality
pancreatic ductal cell	CL:0002079	94.32	gold quality
lower esophagus mucosa	UBERON:0035834	94.30	gold quality
heart	UBERON:0000948	94.11	gold quality
body of stomach	UBERON:0001161	94.05	gold quality
muscle organ	UBERON:0001630	94.03	gold quality
esophagus mucosa	UBERON:0002469	93.87	gold quality
minor salivary gland	UBERON:0001830	93.80	gold quality
small intestine	UBERON:0002108	93.42	gold quality
saliva-secreting gland	UBERON:0001044	93.39	gold quality
body of pancreas	UBERON:0001150	93.10	gold quality
granulocyte	CL:0000094	92.81	gold quality
vena cava	UBERON:0004087	92.45	gold quality
esophagus	UBERON:0001043	92.30	gold quality
mouth mucosa	UBERON:0003729	92.28	gold quality
monocyte	CL:0000576	92.13	gold quality
mononuclear cell	CL:0000842	91.93	gold quality
skin of leg	UBERON:0001511	91.77	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.79

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

58 targets.

Target	Regulation
ACADM	Unknown
ADAM2
AHR	Unknown
APOA4	Unknown
BGLAP	Unknown
CD74
CEL
CIDEA	Activation
CYC1
CYCS	Activation
CYP19A1	Activation
DAP3	Unknown
ESR1	Activation
ESRRA	Unknown
GCK	Unknown
GFM1
GK
GNAS
IBSP	Unknown
KLK3
LDHB	Activation
LTF	Unknown
MAOB
MFN2	Unknown
NOS3	Unknown
NOTCH1
NR0B1	Unknown
NR0B2	Activation
NR1D1	Activation
NR2F1	Repression

JASPAR motifs

Motif	Name	Family
MA0592.1	ESRRA	Steroid hormone receptors (NR3)
MA0592.3	ESRRA	Steroid hormone receptors (NR3)
MA0592.4	ESRRA	Steroid hormone receptors (NR3)

JASPAR matrix evidence (PMIDs): PMID:17488637

Upstream regulators (CollecTRI, top): AR, ESR1, ESRRA, ESRRG, PPARG, RBCK1

miRNA regulators (miRDB)

29 targeting ESRRA, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-365A-3P	99.43	70.02	836
HSA-MIR-365B-3P	99.43	70.02	836
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-135A-5P	99.36	71.85	1601
HSA-MIR-135B-5P	99.36	71.63	1613
HSA-MIR-12135	98.99	70.26	1814
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-6516-5P	98.42	70.19	1551
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-5007-5P	97.95	64.71	614
HSA-MIR-8055	97.62	66.09	1023
HSA-MIR-4653-3P	96.26	67.03	725
HSA-MIR-423-3P	95.99	67.75	62

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 13.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• ERRalpha1 can play a critical role in the etiology of some breast cancers (PMID:11986328)
• directly associates with PGC-1(ALPHA) and has a similar pattern of expression (PMID:12397057)
• ERRalpha has a role in the induction of fatty acid oxidation enzyme MCAD by PGC-1 in human cells (PMID:12522104)
• interacts with a conserved domain of EBNA-LP (Epstein-Barr virus nuclear antigen-leader protein) that is critical for Epstein-Barr virus-induced B-cell immortalization (PMID:12560563)
• VEGF-A is an estrogen responsive gene and modulation of this gene expression by estrogen is biphasic and can be mediated through ER-alpha dependent pathway. (PMID:12579315)
• ERR alpha 1 has a potential role in the regulation of eNOS expression and may stimulate NO production by endothelial cells (PMID:14610283)
• an interdependent ERRalpha/PGC-1alpha-based transcriptional pathway targets the ESRRA23 element to dictate ERRalpha expression level; regulatory polymorphism studied may provide differential responses to ERRalpha/PGC-1alpha-mediated metabolic cues (PMID:14978033)
• ERRalpha possibly modulates the expression of ERE-containing estrogen-responsive genes, and ERRalpha immunoreactivity is a potent prognostic factor in human breast carcinoma. (PMID:15231680)
• study of the crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha (PMID:15337744)
• 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)
• Data demonstrate that the multi-hormone response element of the estrogen-related receptor-alpha (ERRalpha) gene is a target for ERRgamma transactivation, which is enhanced by peroxisome proliferator-activated receptor-gamma coactivator-1alpha. (PMID:15821111)
• a polymorphism of ESSRA may have a role in regulating lumbar spine bone mineral density (PMID:15883633)
• A single nucleotide in an ERRalpha binding site can determine specific configuration to the receptor and productive interaction with the coactivator PGC-1alpha. (PMID:16150865)
• Up-regulation of estrogen-related receptor alpha is associated with endometrial adenocarcinoma (PMID:16681769)
• analysis of estrogen receptor-related receptor-alpha-cofactor interactions (PMID:17053040)
• enhanced expression of ERRalpha might play a role in the development of human prostate cancer and serve as a significant prognostic factor for the disease (PMID:17294452)
• Our results indicate that EFP functions as a cofactor for ERalpha-mediated transcription. (PMID:17418098)
• Our results indicate an essential role for ERRalpha as a key regulator of oxidative metabolism. (PMID:17418099)
• Although ERRalpha is not directly related to growth of ovarian cancer, ERRalpha is a candidate for prognostic factors for ovarian cancer. (PMID:17509876)
• analysis of human estrogen-related receptor alpha in complex with a synthetic inverse agonist (PMID:17556356)
• ERR alpha can be deactivated by the synthetic molecule XCT790. Here we demonstrate that this compound also induces a proteasome degradation of ERR alpha (PMID:17631492)
• 17beta-estradiol induces ERRalpha gene expression in MCF-7 cells through active recruitment of co-activators and release of co-repressors when ERRalpha and AP1 bind and ERalpha is tethered to the multiple hormone-response element (PMID:18174157)
• ERRalpha (estrogen-related receptor alpha estrogen receptor-like 1) mRNA levels decreased from normal vagina of the pre-menopausal women to atrophic vaginal tissue in post-menopausal women (PMID:18328649)
• These findings reveal a new function for TNNI2 as a co-activator of ERRalpha. (PMID:18331830)
• The association between LRP5 V667M and LS BMD is confirmed but not that between ESRRA repeats and LS BMD. (PMID:18418639)
• 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)
• Results describe the mapping of the nucleosome positions of the estrogen-related receptor alpha gene promoter and examine the changes of histone acetylation in response to peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression. (PMID:18673300)
• ERRalpha activates the expression of androgen response elements (ARE)-containing promoters, such as that of the prostate cancer marker PSA, in an ARE-dependent manner. (PMID:18697814)
• The importance of ERRalpha for adaptive energy metabolism suggest that strategies targeting ERRalpha may be useful in fighting metabolic diseases. (PMID:18778951)
• results confirm a role for ERRalpha in breast cancer growth and highlight it as a potential therapeutic target for estrogen receptor-negative breast cancer (PMID:18974123)
• Results implicate PGC-1alpha and ERRalpha in the pathophysiology of human heart failure. (PMID:19061896)
• A positive correlation between ERRalpha and c-myc at the transcriptional level and statistically significant positive correlation between aromatase and the ERRalpha at protein level, is demonstrated. (PMID:19138740)
• Kaempferol is an estrogen-related receptor alpha inverse agonist. (PMID:19171140)
• cAMP/PKA signaling enhances ERRalpha phosphorylation and nuclear localization, recruitment to the SP-A promoter, and interaction with PKAcat and SRC-2, resulting in the up-regulation of SP-A gene transcription. (PMID:19264843)
• A subset of genes involved in ERRalpha signaling in vitro were evaluated and confirmed in vivo by studying uterine gene expression profiles. (PMID:19276159)
• DHEA production is regulated by PGC-1alpha, ERRalpha, and HNF4alpha (PMID:19389810)
• Data show that activation of estrogen-related receptor alpha in several different breast cancer cell lines leads to a significant increase in VEGF mRNA expression, an activity that translates into an increase in VEGF protein secretion. (PMID:19429439)
• ERRalpha/AIB1 complexes may control estradiol-regulated genes in a hormone-independent manner (PMID:19491275)
• Down regulation of ERRalpha expression inhibits cell proliferation. (PMID:19546226)
• role in bone mass regulation by affecting osteoblastic differentiation (PMID:19608650)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	esrra	ENSDARG00000069266
mus_musculus	Esrra	ENSMUSG00000024955
rattus_norvegicus	Esrra	ENSRNOG00000021139
drosophila_melanogaster	ERR	FBGN0035849

Paralogs (8): PGR (ENSG00000082175), ESR1 (ENSG00000091831), NR3C1 (ENSG00000113580), ESRRB (ENSG00000119715), ESR2 (ENSG00000140009), NR3C2 (ENSG00000151623), AR (ENSG00000169083), ESRRG (ENSG00000196482)

Protein

Protein identifiers

Steroid hormone receptor ERR1 — P11474 (reviewed: P11474)

Alternative names: Estrogen receptor-like 1, Estrogen-related receptor alpha, Nuclear receptor subfamily 3 group B member 1

All UniProt accessions (6): P11474, A0A6E1WCP9, F5GWT5, F5H0E9, H0YGT3, Q569H8

UniProt curated annotations — full annotation on UniProt →

Function. Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5’-TNAAGGTCA-3’. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Induces the expression of PERM1 in the skeletal muscle.

Subunit / interactions. Binds DNA as a monomer or a homodimer. Interacts (via the AF2 domain) with coactivator PPARGC1A (via the L3 motif); the interaction greatly enhances transcriptional activity of genes involved in energy metabolism. Interacts with PIAS4; the interaction enhances sumoylation. Interacts with MAPK15; promotes re-localization of ESRRA to the cytoplasm through a XPO1-dependent mechanism then inhibits ESRRA transcriptional activity.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Phosphorylation on Ser-19 enhances sumoylation on Lys-14 increasing repression of transcriptional activity. Sumoylated with SUMO2. Main site is Lys-14 which is enhanced by phosphorylation on Ser-19, cofactor activation, and by interaction with PIAS4. Sumoylation enhances repression of transcriptional activity, but has no effect on subcellular location nor on DNA binding. Reversibly acetylated. Acetylation by PCAF/KAT2 at Lys-129, Lys-138, Lys-160 and Lys-162 and PCAF/KAT2 decreases transcriptional activity probably by inhibiting DNA-binding activity; deacetylation involves SIRT1 and HDAC8 and increases DNA-binding.

Induction. Induced by PGC1alpha in a number of specific cell types including heart, kidney and muscle.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P11474-1	1	yes
P11474-2	2

RefSeq proteins (3): NP_001269379, NP_001269380, NP_004442* (*=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 (60 total): mutagenesis site 22, helix 12, modified residue 6, cross-link 4, strand 3, region of interest 3, zinc finger region 2, turn 2, chain 1, domain 1, DNA-binding region 1, splice variant 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3K6P	X-RAY DIFFRACTION	2
3D24	X-RAY DIFFRACTION	2.11
2PJL	X-RAY DIFFRACTION	2.3
1XB7	X-RAY DIFFRACTION	2.5
7E2E	X-RAY DIFFRACTION	2.7
9LVP	X-RAY DIFFRACTION	2.79

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11474-F1	78.25	0.58

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): 124 (required for dna-dependent dimerization)

Post-translational modifications (10): 19, 22, 129, 138, 160, 162, 14, 189, 403, 403

Mutagenesis-validated functional residues (22):

Position	Phenotype
14	some loss of sumoylation. complete loss of sumoylation; when associated with r-403.
19	50% loss of phosphorylation but represses transactivation activity in the absence of coactivator. almost complete loss o
19	represses transactivation activity in response to coactivator as for wild type; when associated with d-22.
22	15% loss of phosphorylation but little transactivating activity. almost complete loss of phosphorylation and 2-fold loss
22	represses transactivation activity in response to coactivator as for wild type; when associated with d-19.
118	binds dna as a monomer or as a dimer as for wild type. no effect on interaction with ppargc1a.
124	binds dna predominantly as a monomer. loss of interaction with ppargc1a.
129	abolishes acetylation by pcaf/kat2b; when associated with r-138, r-160 and r-162.
138	abolishes acetylation by pcaf/kat2b; when associated with r-129, r-160 and r-162.
160	abolishes acetylation by pcaf/kat2b; when associated with r-129, r-138 and r-162.
162	abolishes acetylation by pcaf/kat2b; when associated with r-129, r-138 and r-160.
258–262	almost complete loss of interaction to l2 or to l3 of ppargc1a.
259	little effect on binding l2 of ppargc1a. greatly reduced binding to l3 of ppargc1a.
315	almost complete loss of interaction to l2 or to l3 of ppargc1a.
338	almost complete loss of interaction to l2 or to l3 of ppargc1a.
341	little effect on binding l3 of ppargc1a.
343	no effect on binding l3 of ppargc1a.
403	decrease in sumoylation. no effect on transcriptional activity. complete loss of sumoylation; when associated with r-14.
413	loss of coactivation activity; when associated with a-418. loss of increased response to coactivator; when associated wi
418	loss of coactivation activity; when associated with a-413. loss of increased response to coactivator activity; when asso
421–423	greatly reduced interaction with l3 motif of ppargc1a. less effect on binding to l2 motif of ppargc1a.
423	little effect on binding l3 of ppargc1a.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-383280	Nuclear Receptor transcription pathway
R-HSA-8939902	Regulation of RUNX2 expression and activity

MSigDB gene sets: 215 (showing top): AAGCAAT_MIR137, PAX4_01, TGCGCANK_UNKNOWN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, AAGCCAT_MIR135A_MIR135B, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, AP4_Q6, TGACCTY_ERR1_Q2, AP2_Q3, MODULE_16, chr11q13, CAGCTG_AP4_Q5, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY

GO Biological Process (7): regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of gene expression (GO:0010468), nuclear receptor-mediated steroid hormone signaling pathway (GO:0030518), intracellular receptor signaling pathway (GO:0030522)

GO Molecular Function (16): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), 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), protein domain specific binding (GO:0019904), estrogen response element binding (GO:0034056), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): chromatin (GO:0000785), fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), microtubule cytoskeleton (GO:0015630), intercellular bridge (GO:0045171)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Regulation of lipid metabolism by PPARalpha	1
Mitochondrial biogenesis	1
Generic Transcription Pathway	1
Transcriptional regulation by RUNX2	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
transcription by RNA polymerase II	3
regulation of transcription by RNA polymerase II	3
DNA-binding transcription factor activity, RNA polymerase II-specific	3
regulation of DNA-templated transcription	2
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
negative regulation of DNA-templated transcription	1
gene expression	1
regulation of macromolecule biosynthetic process	1
steroid hormone receptor signaling pathway	1
nuclear receptor-mediated signaling pathway	1
intracellular signal transduction	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription repressor activity	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
nuclear receptor activity	1
nuclear receptor-mediated steroid hormone signaling pathway	1
intracellular receptor signaling pathway	1
signaling receptor activity	1
ligand-modulated transcription factor activity	1
lipid binding	1
transition metal ion binding	1
protein binding	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
cation binding	1

Protein interactions and networks

STRING

2064 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ESRRA	PPARGC1A	Q9UBK2	998
ESRRA	PPARGC1B	Q86YN6	970
ESRRA	PPARG	P37231	873
ESRRA	SLC7A1	P30825	847
ESRRA	NRIP1	P48552	745
ESRRA	TFAM	Q00059	728
ESRRA	NRF1	Q16656	706
ESRRA	KLF4	P78338	692
ESRRA	GABPA	Q06546	686
ESRRA	YY1	P25490	668
ESRRA	GABPB1	Q06547	661
ESRRA	PPARA	Q07869	636
ESRRA	NCOR1	O75376	617
ESRRA	SIRT1	Q96EB6	601
ESRRA	SIRT3	Q9NTG7	596

IntAct

88 interactions, top by confidence:

A	B	Type	Score
ESRRA	PPARGC1A	psi-mi:“MI:0407”(direct interaction)	0.890
ESRRA	PPARGC1A	psi-mi:“MI:0915”(physical association)	0.890
PPARGC1A	ESRRA	psi-mi:“MI:0915”(physical association)	0.890
ESRRA	HIF1A	psi-mi:“MI:0915”(physical association)	0.580
HIF1A	ESRRA	psi-mi:“MI:0915”(physical association)	0.580
PIAS4	ESRRA	psi-mi:“MI:0915”(physical association)	0.570
ESRRA	PIAS4	psi-mi:“MI:0915”(physical association)	0.570
ESRRA	TNNI2	psi-mi:“MI:0915”(physical association)	0.560
ESRRA	REL	psi-mi:“MI:0915”(physical association)	0.560
ESRRA	FAM9A	psi-mi:“MI:0915”(physical association)	0.560
ESRRA	ESRRG	psi-mi:“MI:0915”(physical association)	0.560
ESRRA	RNF4	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (102): ESRRA (Two-hybrid), NCOA1 (Two-hybrid), PSMC5 (Two-hybrid), ESRRA (Affinity Capture-MS), ESRRA (Affinity Capture-MS), ESRRA (Affinity Capture-RNA), ESRRA (Reconstituted Complex), HIF1A (Affinity Capture-Western), ESRRA (Affinity Capture-Western), MTDH (Affinity Capture-Western), ESRRA (Two-hybrid), ESRRA (Two-hybrid), ESRRA (Two-hybrid), ESRRA (Two-hybrid), FAM9A (Two-hybrid)

ESM2 similar proteins: A3KN25, A6H687, A6NE52, A6NKF1, A6QQ91, A8MYJ7, D2HS90, E1BD59, O08580, O09017, O75064, O75427, O94812, P0C5W1, P11474, P43136, P52824, P58660, Q08DF2, Q08DM2, Q1JPD6, Q2TBW5, Q3U0S6, Q3U1Y4, Q562E7, Q5BK61, Q5JR98, Q5JZY3, Q5QJV7, Q5U651, Q6F5E8, Q6QMY5, Q86YV0, Q8BYG9, Q8C052, Q8C2K5, Q8CDY7, Q8R5G7, Q8WWN8, Q96HA7

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

8 interactions.

A	Effect	B	Mechanism
ESRRA	“down-regulates quantity by repression”	SNAI2	“transcriptional regulation”
ESRRA	“up-regulates quantity by expression”	CYP19A1	“transcriptional regulation”
ESRRA	“down-regulates quantity by repression”	NR2F1	“transcriptional regulation”
ESRRA	“down-regulates quantity by repression”	NR2F6	“transcriptional regulation”
ESRRA	“down-regulates quantity by repression”	SNAI1	“transcriptional regulation”
ESRRA	“up-regulates quantity by expression”	RNF208	“transcriptional regulation”
DPF2	“down-regulates activity”	ESRRA	binding
PPARGC1A	“up-regulates activity”	ESRRA

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 39 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
SUMOylation of transcription cofactors	6	56.1×	1e-07

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — ACYC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1300 predictions. Top by Δscore:

Variant	Effect	Δscore
11:64307333:G:GT	donor_gain	1.0000
11:64307503:GG:G	donor_gain	1.0000
11:64307504:GG:G	donor_gain	1.0000
11:64313945:T:TA	acceptor_gain	1.0000
11:64314063:GGAGG:G	donor_gain	1.0000
11:64314064:GAGGG:G	donor_gain	1.0000
11:64314065:A:T	donor_gain	1.0000
11:64314066:GG:G	donor_gain	1.0000
11:64314067:GG:G	donor_gain	1.0000
11:64314231:A:AG	acceptor_gain	1.0000
11:64314236:AAGG:A	acceptor_loss	1.0000
11:64314237:A:G	acceptor_gain	1.0000
11:64314238:G:GC	acceptor_loss	1.0000
11:64314238:GGA:G	acceptor_gain	1.0000
11:64314730:A:AG	acceptor_gain	1.0000
11:64314735:TCACA:T	acceptor_loss	1.0000
11:64314736:CACA:C	acceptor_loss	1.0000
11:64314738:CA:C	acceptor_loss	1.0000
11:64314738:CAGCA:C	acceptor_gain	1.0000
11:64314739:A:AG	acceptor_gain	1.0000
11:64314739:AGCAG:A	acceptor_gain	1.0000
11:64314740:G:GA	acceptor_gain	1.0000
11:64314740:GC:G	acceptor_gain	1.0000
11:64314740:GCA:G	acceptor_gain	1.0000
11:64314740:GCAGC:G	acceptor_gain	1.0000
11:64314908:CCAG:C	donor_loss	1.0000
11:64314910:AG:A	donor_loss	1.0000
11:64314911:GGTA:G	donor_loss	1.0000
11:64314912:G:A	donor_loss	1.0000
11:64314913:T:A	donor_loss	1.0000

AlphaMissense

2669 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:64307414:T:A	C79S	1.000
11:64307414:T:C	C79R	1.000
11:64307415:G:A	C79Y	1.000
11:64307415:G:C	C79S	1.000
11:64307415:G:T	C79F	1.000
11:64307416:C:G	C79W	1.000
11:64307421:T:A	V81D	1.000
11:64307423:T:A	C82S	1.000
11:64307423:T:C	C82R	1.000
11:64307424:G:A	C82Y	1.000
11:64307424:G:C	C82S	1.000
11:64307424:G:T	C82F	1.000
11:64307425:T:G	C82W	1.000
11:64307429:G:C	D84H	1.000
11:64307429:G:T	D84Y	1.000
11:64307430:A:C	D84A	1.000
11:64307430:A:G	D84G	1.000
11:64307430:A:T	D84V	1.000
11:64307436:C:A	A86D	1.000
11:64307436:C:T	A86V	1.000
11:64307439:C:A	S87Y	1.000
11:64307439:C:T	S87F	1.000
11:64307441:G:A	G88S	1.000
11:64307441:G:C	G88R	1.000
11:64307441:G:T	G88C	1.000
11:64307442:G:A	G88D	1.000
11:64307442:G:T	G88V	1.000
11:64307447:C:A	H90N	1.000
11:64307447:C:G	H90D	1.000
11:64307447:C:T	H90Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000415828 (11:64313626 T>C), RS1000553878 (11:64305327 G>T), RS1000689952 (11:64306201 T>C), RS1001840955 (11:64304310 C>T), RS1001910761 (11:64306322 G>A), RS1002797864 (11:64308104 C>T), RS1002975702 (11:64315330 AGTGACG>A), RS1003549748 (11:64317152 G>A,T), RS1003590279 (11:64303733 T>A), RS1004217296 (11:64310075 T>C), RS1004281526 (11:64309136 CAAAAAA>C,CAA,CAAAA,CAAAAA,CAAAAAAA), RS1004312826 (11:64308429 A>G), RS1004462251 (11:64316157 CGT>C), RS1004516850 (11:64304602 G>C), RS1004654094 (11:64304362 C>T)

Disease associations

OMIM: gene MIM:601998 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000879_54	Crohn’s disease	6.000000e-10
GCST004132_98	Crohn’s disease	5.000000e-06
GCST004785_38	Vitiligo	5.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3429 (SINGLE PROTEIN), CHEMBL4296142 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523749 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 421,522 (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
CHEMBL1358	FULVESTRANT	4	56,655
CHEMBL83	TAMOXIFEN	4	171,635
CHEMBL44	GENISTEIN	2	44,212
CHEMBL150	KAEMPFEROL	1	25,940

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 (3 total), top 3:

Ligand	Action	Affinity	Parameter
compound 1a [PMID: 17556356]	Inverse agonist	6.7	pIC50
XCT790	Antagonist	6.5	pIC50
diethylstilbestrol	Antagonist	5.3	pIC50

Binding affinities (BindingDB)

48 measured of 60 human assays (60 total across all organisms); most potent 48 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
(cyclohexylmethyl)({[1-(4-methylphenyl)-1H-indol-3-yl]methyl})amine	IC50	190 nM
6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-1-one	KI	252 nM	US-9623021: Nuclear receptor binding agents
3-((R)-7-((1-(4-((3S,4R)-7-hydroxy-3- phenylchroman-4-yl)phenyl)piperidin-4- yl)methyl)-1-oxo-1,3,5,5a,6,7,8,9- octahydro-2H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- e]isoindol-2-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
3-((R)-7-((1-(2-fluoro-4-((3S,4R)-7- hydroxy-3-phenylchroman-4- yl)phenyl)piperidin-4-yl)methyl)-1-oxo- 1,3,5,5a,6,7,8,9-octahydro-2H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- e]isoindol-2-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
2-(2,6-dioxopiperidin-3-yl)-6-(2-(7-(4- ((3S,4R)-7-hydroxy-3-phenylchroman-4- yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)- 2-oxoethyl)-6,7-dihydropyrrolo[3,4- f]isoindole-1,3(2H,5H)-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
3-((R)-7-((1-(5-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)pyrimidin-2- yl)piperidin-4-yl)methyl)-1-oxo- 1,3,5,5a,6,7,8,9-octahydro-2H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- elisoindol-2-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
2-(2,6-dioxopiperidin-3-yl)-6-(2-(9-(4- ((3R,4S)-7-hydroxy-3-phenylchroman-4- yl)phenyl)-3,9-diazaspiro[5.5]undecan-3- yl)-2-oxoethyl)-6,7-dihydropyrrolo[3,4- f]isoindole-1,3(2H,5H)-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(R)-3-(6-(2-(9-(4-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-3,9- diazaspiro[5.5]undecan-3-yl)acetyl)-1- oxo-3,5,6,7-tetrahydropyrrolo[3,4- f]isoindol-2(1H)-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
2-(2,6-dioxopiperidin-3-yl)-6-(2-(2-(4- ((3S,4R)-7-hydroxy-3-phenylchroman-4- yl)phenyl)-2,7-diazaspiro[3.5]nonan-7-yl)- 2-oxoethyl)-6,7-dihydropyrrolo[3,4- f]isoindole-1,3(2H,5H)-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
3-(6-(2-(2-(4-((3S,4R)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-2,7- diazaspiro[3.5]nonan-7-yl)acetyl)-1-oxo- 3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol- 2(1H)-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(S)-3-((R)-7-((7-(4-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-7- azaspiro[3.5]nonan-2-yl)methyl)-1-oxo- 1,3,5,5a,6,7,8,9-octahydro-2H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- e]isoindol-2-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
3-(6-(2-(7-(4-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-2,7- diazaspiro[3.5]nonan-2-yl)acetyl)-1-oxo- 3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol- 2(1H)-yl)piperidine-2,6-dione formate	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(S)-3-((S)-3-((7-(4-((3S,4R)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-7- azaspiro[3.5]nonan-2-yl)methyl)-8-oxo- 1,2,3,4,4a,5,8,10-octahydro-9H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- f]isoindol-9-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3- phenylchroman-4-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
3-((R)-7-((1-(5-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)pyridin-2- yl)piperidin-4-yl)methyl)-1-oxo- 1,3,5,5a,6,7,8,9-octahydro-2H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- e]isoindol-2-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
3-(1’-((2-(4-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-2- azaspiro[3.5]nonan-7-yl)methyl)-7-oxo- 5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4’-piperidin]-6-yl)piperidine- 2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(S)-3-((R)-7-((2-(4-((3S,4R)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-2- azaspiro[3.5]nonan-7-yl)methyl)-1-oxo- 1,3,5,5a,6,7,8,9-octahydro-2H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- e]isoindol-2-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(R)-3-((R)-3-((1-(4-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)-3- methoxyphenyl)piperidin-4-yl)methyl)-8- oxo-1,2,3,4,4a,5,8,10-octahydro-9H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- f]isoindol-9-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(R)-3-((S)-7-((7-(2-fluoro-4-((3S,4S)-7- hydroxy-3-phenylchroman-4-yl)-5- methoxyphenyl)-7-azaspiro[3.5]nonan-2- yl)methyl)-1-oxo-1,3,5,5a,6,7,8,9- octahydro-2H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- e]isoindol-2-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
3-(1’-((7-(2-fluoro-4-((3R,4R)-7-hydroxy- 3-phenylchroman-4-yl)-5- methoxyphenyl)-7-azaspiro[3.5]nonan-2- yl)methyl)-6-oxo-6,8-dihydro-2H,7H- spiro[furo[2,3-e]isoindole-3,4’-piperidin]- 7-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(3R)-3-((4aR)-3-((8-(4-((3R,4S)-7- hydroxy-3-phenylchroman-4-yl)phenyl)-1- oxa-8-azaspiro[4.5]decan-3-yl)methyl)-8- oxo-1,2,3,4,4a,5,8,10-octahydro-9H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- f]isoindol-9-yl)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(R)-3-((4-(1-((1-(4-((3S,4R)-7-hydroxy-3- phenylchroman-4-yl)-3- methoxyphenyl)piperidin-4- yl)methyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(R)-3-(1’-((2-(4-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-2- azaspiro[3.5]nonan-7-yl)methyl)-7-oxo- 5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4’-piperidin]-6-yl)piperidine- 2,6-dione	IC50	275 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(cyclohexylmethyl)[(1-phenyl-1H-indol-3-yl)methyl]amine	IC50	700 nM
6-hydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-1-one	KI	2100 nM	US-9604931: Nuclear receptor binding agents
3-((S)-3-((7-(4-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-7- azaspiro[3.5]nonan-2-yl)methyl)-8-oxo- 1,2,3,4,4a,5,8,10-octahydro-9H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- f]isoindol-9-yl)piperidine-2,6-dione	IC50	2750 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
3-((S)-3-((2-(4-((3S,4R)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-2- azaspiro[3.5]nonan-7-yl)methyl)-8-oxo- 1,2,3,4,4a,5,8,10-octahydro-9H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- f]isoindol-9-yl)piperidine-2,6-dione	IC50	2750 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
3-((R)-7-((1-(4-((3S,4R)-7-hydroxy-3- phenylchroman-4-yl)-3- methoxyphenyl)piperidin-4-yl)methyl)-1- oxo-1,3,5,5a,6,7,8,9-octahydro-2H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- e]isoindol-2-yl)piperidine-2,6-dione	IC50	2750 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
3-(6-(1’-(4-((3S,4R)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-[1,4’- bipiperidine]-4-carbonyl)-1-oxo-3,5,6,7- tetrahydropyrrolo[3,4-f]isoindol-2(1H)- yl)piperidine-2,6-dione	IC50	2750 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
3-((R)-3-((1-(4-((3S,4R)-7-hydroxy-3- phenylchroman-4-yl)-3- methoxyphenyl)piperidin-4-yl)methyl)-8- oxo-1,2,3,4,4a,5,8,10-octahydro-9H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- f]isoindol-9-yl)piperidine-2,6-dione	IC50	2750 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
rac-N-(2,6-dioxopiperidin-3-yl)-5-(4-((2- (4-((3R,4S)-7-hydroxy-3-phenylchroman- 4-yl)phenyl)-2-azaspiro[3.5]nonan-7- yl)methyl)piperazin-1-yl)-4- methoxypicolinamide	IC50	2750 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(R)-3-((R)-3-((2-(4-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-2- azaspiro[3.5]nonan-7-yl)methyl)-8-oxo- 1,2,3,4,4a,5,8,10-octahydro-9H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- f]isoindol-9-yl)piperidine-2,6-dione	IC50	2750 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(R)-3-((S)-3-((2-(4-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-2- azaspiro[3.5]nonan-7-yl)methyl)-8-oxo- 1,2,3,4,4a,5,8,10-octahydro-9H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- f]isoindol-9-yl)piperidine-2,6-dione	IC50	2750 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(R)-3-((S)-7-((1-(4-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)-3- methoxyphenyl)piperidin-4-yl)methyl)-1- oxo-1,3,5,5a,6,7,8,9-octahydro-2H- pyrazino[1’,2’:4,5][1,4]oxazino[2,3- e]isoindol-2-yl)piperidine-2,6-dione	IC50	2750 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(R)-3-((4-(1-((2-(4-((3R,4S)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-2- azaspiro[3.5]nonan-7-yl)methyl)piperidin- 4-yl)phenyl)amino)piperidine-2,6-dione	IC50	2750 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(R)-N-((S)-2,6-dioxopiperidin-3-yl)-3-((2- (4-((3S,4R)-7-hydroxy-3-phenylchroman- 4-yl)phenyl)-2-azaspiro[3.5]nonan-7- yl)methyl)-1,2,3,4,4a,5- hexahydropyrazino[1,2-d]pyrido[2,3- b][1,4]oxazine-8-carboxamide	IC50	2750 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
(R)-N-((S)-2,6-dioxopiperidin-3-yl)-3- (((S)-8-(4-((3S,4R)-7-hydroxy-3- phenylchroman-4-yl)phenyl)-1-oxa-8- azaspiro[4.5]decan-3-yl)methyl)- 1,2,3,4,4a,5-hexahydropyrazino[1,2- d]pyrido[2,3-b][1,4]oxazine-8- carboxamide	IC50	2750 nM	US-20260000676: CHROMAN DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS

ChEMBL bioactivities

259 potent at pChembl≥5 of 262 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	IC50	2	nM	FULVESTRANT
8.48	IC50	3.3	nM	CHEMBL402491
8.44	IC50	3.6	nM	ESTRADIOL
8.44	IC50	3.6	nM	CHEMBL250097
8.37	IC50	4.3	nM	CHEMBL198411
8.36	IC50	4.33	nM	CHEMBL4533857
8.36	IC50	4.33	nM	CHEMBL4578651
8.34	IC50	4.6	nM	CHEMBL372783
8.33	IC50	4.67	nM	CHEMBL4440692
8.30	IC50	5	nM	CHEMBL4170306
8.27	IC50	5.33	nM	CHEMBL4543370
8.27	IC50	5.33	nM	CHEMBL4467767
8.25	IC50	5.67	nM	CHEMBL4514580
8.25	IC50	5.67	nM	CHEMBL4445475
8.23	EC50	5.9	nM	ESTRADIOL
8.22	IC50	6	nM	ESTRADIOL
8.22	IC50	6	nM	CHEMBL4444248
8.21	IC50	6.1	nM	CHEMBL402492
8.20	IC50	6.33	nM	CHEMBL4456486
8.15	IC50	7	nM	CHEMBL4521251
8.13	IC50	7.33	nM	CHEMBL4461157
8.12	IC50	7.67	nM	CHEMBL4532018
8.10	IC50	8	nM	CHEMBL4169272
8.10	IC50	8	nM	CHEMBL4161346
8.10	IC50	8	nM	CHEMBL4166492
8.10	IC50	8	nM	CHEMBL4218019
8.05	IC50	9	nM	CHEMBL4159613
8.05	IC50	9	nM	CHEMBL4163909
8.03	IC50	9.33	nM	CHEMBL4538025
8.00	IC50	10	nM	GENISTEIN
7.95	IC50	11.33	nM	CHEMBL4461263
7.92	IC50	12	nM	CHEMBL4166832
7.91	IC50	12.33	nM	CHEMBL4469374
7.90	IC50	12.67	nM	CHEMBL4570799
7.89	IC50	13	nM	CHEMBL4165363
7.89	IC50	13	nM	CHEMBL1671982
7.82	IC50	15	nM	CHEMBL4172209
7.82	IC50	15	nM	CHEMBL4172522
7.80	IC50	16	nM	CHEMBL4163054
7.80	IC50	16	nM	CHEMBL1671969
7.77	IC50	17	nM	CHEMBL4163375
7.75	IC50	18	nM	CHEMBL4173278
7.72	IC50	19	nM	CHEMBL4177113
7.72	IC50	19	nM	CHEMBL4173757
7.69	IC50	20.33	nM	CHEMBL4443118
7.68	IC50	21	nM	CHEMBL2381353
7.66	IC50	22	nM	CHEMBL4093786
7.66	IC50	22	nM	CHEMBL4164196
7.66	IC50	22	nM	CHEMBL250300
7.64	IC50	23	nM	CHEMBL4169919

PubChem BioAssay actives

241 with measured affinity, of 622 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
Fulvestrant	728186: Antagonist activity at ERalpha receptor in human MCF7 cells assessed as inhibition of cell growth after 6 days by crystal violet staining method	ic50	0.0020	uM
7-chloro-6H-chromeno[4,3-b]quinoline-3,9-diol	307629: Inhibition of human ERalpha	ic50	0.0033	uM
7-bromo-6H-chromeno[4,3-b]quinoline-3,9-diol	307629: Inhibition of human ERalpha	ic50	0.0036	uM
Estradiol	307629: Inhibition of human ERalpha	ic50	0.0036	uM
4-bromo-2-(4-hydroxyphenyl)quinolin-6-ol	307629: Inhibition of human ERalpha	ic50	0.0043	uM
(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0043	uM
(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyano-N-(2-methoxyethyl)prop-2-enamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0043	uM
4-chloro-2-(4-hydroxyphenyl)quinolin-6-ol	307629: Inhibition of human ERalpha	ic50	0.0046	uM
3-[2-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]ethoxy]propanoic acid	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0047	uM
(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-3-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-1,3-thiazolidine-2,4-dione	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0050	uM
(2S,4R)-1-[(2S)-2-[3-[2-[2-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]ethoxy]ethoxy]propanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0053	uM
(2S,4S)-1-[(2S)-2-[5-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]pentanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0053	uM
(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoic acid	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0057	uM
(2S,4R)-1-[(2S)-2-[6-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]hexanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0057	uM
5-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]pentanoic acid	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0060	uM
3,9-dihydroxy-6H-chromeno[4,3-b]quinoline-7-carbonitrile	307629: Inhibition of human ERalpha	ic50	0.0061	uM
(2S,4R)-1-[(2S)-2-[4-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]butanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0063	uM
(2S,4R)-1-[(2S)-2-[3-[2-[2-[2-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]ethoxy]ethoxy]ethoxy]propanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0070	uM
(2S,4R)-1-[(2S)-2-[3-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]propanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0073	uM
(2S,4R)-1-[(2S)-2-[8-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]octanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0077	uM
N-[[(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]methylsulfonyl]acetamide	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0080	uM
4-[(5Z)-5-[[1-[[4-methoxy-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]cyclohexane-1-carboxylic acid	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0080	uM
(5Z)-5-[[1-[[4-methoxy-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-3-(2-morpholin-4-ylethyl)-1,3-thiazolidine-2,4-dione	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0080	uM
(2S,4R)-1-[(2S)-2-[3-[2-[(5Z)-5-[[4-[4-cyano-2-(trifluoromethyl)phenoxy]-3-methoxyphenyl]methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]ethoxy]propanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0080	uM
2-[(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0090	uM
2-[(5Z)-5-[[1-[[4-methoxy-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0090	uM
(2S,4R)-1-[(2S)-2-[3-[2-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]ethoxy]propanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0093	uM
Genistein	307629: Inhibition of human ERalpha	ic50	0.0100	uM
(2S,4R)-1-[(2S)-2-[[2-[2-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0113	uM
4-[(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]cyclohexane-1-carboxylic acid	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0120	uM
(2S,4R)-1-[(2S)-2-[7-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]heptanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0123	uM
(2S,4R)-1-[(2S)-2-[5-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]pentanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0127	uM
methyl 4-[4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-methoxyphenoxy]naphthalene-1-carboxylate	569735: Antagonist activity at 6his-tagged ERRalpha LBD assessed as inhibition of recruitment of GST-labeled coactivator Scr2 by TR-FRET assay	ic50	0.0130	uM
(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-3-(2H-tetrazol-5-ylmethyl)-1,3-thiazolidine-2,4-dione	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0130	uM
(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-3-[1-(2-hydroxyethyl)piperidin-4-yl]-1,3-thiazolidine-2,4-dione	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0150	uM
(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-3-[[(3S)-morpholin-3-yl]methyl]-1,3-thiazolidine-2,4-dione	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0150	uM
methyl 4-[4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-methoxyphenoxy]-3-(trifluoromethyl)benzoate	569735: Antagonist activity at 6his-tagged ERRalpha LBD assessed as inhibition of recruitment of GST-labeled coactivator Scr2 by TR-FRET assay	ic50	0.0160	uM
(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0160	uM
(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0170	uM
2-[(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]-N-methylsulfonylacetamide	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0180	uM
2-[(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]-N-sulfamoylacetamide	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0190	uM
(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-3-(1-methylpiperidin-4-yl)-1,3-thiazolidine-2,4-dione	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0190	uM
methyl (E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoate	1509384: Binding affinity to GST-tagged ERRalpha-LBD (unknown origin) using fluorescein-conjugated coactivator PGC-1alpha incubated for 1 hr by TR-FRET assay	ic50	0.0203	uM
(2-aminophenyl)-[1-(3-propan-2-ylphenyl)triazol-4-yl]methanone	748036: Inhibition of human GAL4-DBD-fused ERRalpha-LBD transcriptional activity transfected in human 293FT cells assessed as disruption of interaction with PGC-1alpha after 24 hrs by dual luciferase reporter gene assay	ic50	0.0210	uM
7-ethenyl-6H-chromeno[4,3-b]quinoline-3,9-diol	307629: Inhibition of human ERalpha	ic50	0.0220	uM
1-[6-[(2R)-4-[1-[[3-(2-methoxyethoxy)phenyl]methyl]-3-methylthieno[3,2-d]pyrazole-5-carbonyl]-2-methylpiperazin-1-yl]-3-pyridinyl]ethanone	1430353: Inverse agonist activity at GAL4-fused human ERRalpha expressed in HEK293 cells assessed as inhibition of transcriptional activity after 20 hrs by luciferase reporter gene assay	ic50	0.0220	uM
(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-3-[(3S,4S)-3-fluoro-1-methylpiperidin-4-yl]-1,3-thiazolidine-2,4-dione	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0220	uM
(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-3-[(3R,4R)-3-fluoro-1-methylpiperidin-4-yl]-1,3-thiazolidine-2,4-dione	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0230	uM
(5Z)-3-[(2R)-2-amino-3-hydroxypropyl]-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-1,3-thiazolidine-2,4-dione	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0230	uM
2-[(5Z)-5-[[1-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]indazol-5-yl]methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(dimethylsulfamoyl)acetamide	1499694: Antagonist activity at His6-tagged ERRalpha LBD (unknown origin) assessed as inhibition of GST-tagged SRC-2 co-activator peptide recruitment after 18 hrs by TR-FRET assay	ic50	0.0230	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects binding, increases activity, decreases reaction, increases expression, increases reaction (+2 more)	10
Estradiol	affects expression, affects cotreatment, decreases expression, decreases reaction, increases expression (+2 more)	9
Genistein	affects binding, increases activity, decreases activity, increases expression	5
Toxaphene	decreases reaction, affects binding, decreases activity, increases activity	4
XCT790	decreases expression, decreases activity, decreases reaction	3
Chlordan	affects binding, decreases activity	3
afimoxifene	affects binding, decreases activity	2
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression, affects binding, increases activity	2
Bortezomib	decreases reaction, increases activity, decreases activity, decreases expression	2
Fulvestrant	decreases reaction, increases expression, decreases expression, affects binding, increases reaction	2
Estrogens	increases expression	2
Methotrexate	decreases expression, decreases reaction, increases cleavage, increases expression, decreases response to substance	2
Tamoxifen	affects binding, decreases reaction, increases expression, increases reaction	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	increases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	increases expression	1
TAK-243	decreases sumoylation	1
biochanin A	affects binding, increases activity, increases reaction	1
2,4,6-tribromophenol	decreases expression	1
daidzein	affects binding, increases activity, increases reaction	1
triphenyl phosphate	affects expression	1
metoprine	decreases reaction, increases activity, decreases activity	1
chlormidazole	increases activity, decreases activity, decreases reaction	1
alpha-naphthoflavone	affects binding	1
trichostatin A	increases activity	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	decreases expression	1
aflatoxin B2	increases methylation	1
artemisinin	decreases reaction, increases activity, decreases activity	1

ChEMBL screening assays

105 unique, capped per target: 94 binding, 11 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1008241	Binding	Binding affinity to ERRalpha ligand binding domain by FRET assay	Crystal structure of human estrogen-related receptor alpha in complex with a synthetic inverse agonist reveals its novel molecular mechanism. — J Biol Chem
CHEMBL1679579	Functional	Antagonist activity at 6his-tagged ERRalpha LBD assessed as inhibition of recruitment of GST-labeled coactivator Scr2 by TR-FRET assay	Identification of diaryl ether-based ligands for estrogen-related receptor α as potential antidiabetic agents. — J Med Chem

Cellosaurus cell lines

12 cell lines: 5 cancer cell line, 4 embryonic stem cell, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A1L0	SEES3-1V human ESRRA, clone1	Embryonic stem cell	Male
CVCL_A1L1	SEES3-1V human ESRRA, clone2	Embryonic stem cell	Male
CVCL_A1L2	SEES3-1V human ESRRA, clone3	Embryonic stem cell	Male
CVCL_B8FL	Abcam HCT 116 ESRRA KO	Cancer cell line	Male
CVCL_B9HU	Abcam A-549 ESRRA KO	Cancer cell line	Male
CVCL_BW92	ES-R1 CAG-S-hERRalpha	Embryonic stem cell	Male
CVCL_D2F3	Abcam MCF-7 ESRRA KO	Cancer cell line	Female
CVCL_D9EL	Ubigene HEK293 ESRRA KO	Transformed cell line	Female
CVCL_LF42	GeneBLAzer ERRalpha-UAS-bla HEK 293T	Transformed cell line	Female
CVCL_SM44	HAP1 ESRRA (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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