ESR1

Summary

ESR1 (estrogen receptor 1, HGNC:3467) is a protein-coding gene on chromosome 6q25.1-q25.2, encoding Estrogen receptor (P03372). Nuclear hormone receptor. In precision oncology, ESR1 D538G confers sensitivity to Elacestrant in Estrogen-receptor Positive Breast Cancer (CIViC Level A); 28 further curated variant–drug associations are listed below.

This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain.

Source: NCBI Gene 2099 — RefSeq curated summary.

At a glance

• Gene–disease (curated): estrogen resistance syndrome (Strong, GenCC)
• GWAS associations: 126
• Clinical variants (ClinVar): 221 total — 5 pathogenic
• Phenotypes (HPO): 43
• Druggable target: yes — 162 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 29 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 4 cancer types
• Transcription factor: yes — 721 downstream targets (CollecTRI)
• MANE Select transcript: NM_000125

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3467
Approved symbol	ESR1
Name	estrogen receptor 1
Location	6q25.1-q25.2
Locus type	gene with protein product
Status	Approved
Aliases	ER, NR3A1, Era, ER-alpha
Ensembl gene	ENSG00000091831
Ensembl biotype	protein_coding
OMIM	133430
Entrez	2099

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 14 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000206249, ENST00000338799, ENST00000404742, ENST00000406599, ENST00000415488, ENST00000427531, ENST00000440973, ENST00000443427, ENST00000446550, ENST00000456483, ENST00000473497, ENST00000482101, ENST00000488573, ENST00000641399, ENST00000858333, ENST00000858334, ENST00000858335, ENST00000947759

RefSeq mRNA: 12 — MANE Select: NM_000125 NM_000125, NM_001122740, NM_001122741, NM_001122742, NM_001291230, NM_001291241, NM_001328100, NM_001385568, NM_001385569, NM_001385570, NM_001385571, NM_001385572

CCDS: CCDS5234, CCDS87457

Canonical transcript exons

ENST00000206249 — 8 exons

Exon	Start	End
ENSE00000813753	152011656	152011794
ENSE00001128501	152098732	152103274
ENSE00001877305	151807682	151808364
ENSE00002178920	151944173	151944508
ENSE00003705805	151842597	151842787
ENSE00003721187	151880655	151880771
ENSE00003736522	152094385	152094568
ENSE00003743537	152060991	152061124

Expression profiles

Bgee: expression breadth ubiquitous, 216 present calls, max score 97.49.

FANTOM5 (CAGE): breadth broad, TPM avg 6.0840 / max 443.8041, expressed in 646 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
70636	1.6303	159
70616	1.2472	480
70627	0.5161	166
70628	0.4835	172
70617	0.4010	158
70635	0.3671	126
70615	0.2836	150
70638	0.2349	110
70629	0.2308	99
70631	0.2192	96

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	97.49	gold quality
cervix epithelium	UBERON:0004801	96.89	gold quality
mammalian vulva	UBERON:0000997	96.85	gold quality
endometrium	UBERON:0001295	96.64	gold quality
uterine cervix	UBERON:0000002	96.04	gold quality
cervix squamous epithelium	UBERON:0006922	95.98	gold quality
fallopian tube	UBERON:0003889	95.94	gold quality
endocervix	UBERON:0000458	95.16	gold quality
right uterine tube	UBERON:0001302	94.72	gold quality
uterus	UBERON:0000995	94.53	gold quality
ectocervix	UBERON:0012249	94.34	gold quality
epithelium of mammary gland	UBERON:0003244	94.10	gold quality
mammary duct	UBERON:0001765	93.85	gold quality
body of uterus	UBERON:0009853	93.61	gold quality
vagina	UBERON:0000996	93.35	gold quality
caput epididymis	UBERON:0004358	92.43	gold quality
germinal epithelium of ovary	UBERON:0001304	91.68	gold quality
calcaneal tendon	UBERON:0003701	91.13	gold quality
urethra	UBERON:0000057	90.87	gold quality
myometrium	UBERON:0001296	90.85	gold quality
tibia	UBERON:0000979	90.56	gold quality
mammary gland	UBERON:0001911	89.63	gold quality
thoracic mammary gland	UBERON:0005200	89.62	gold quality
left uterine tube	UBERON:0001303	89.21	gold quality
adult organism	UBERON:0007023	88.52	gold quality
female reproductive system	UBERON:0000474	88.11	gold quality
nipple	UBERON:0002030	86.20	gold quality
tendon	UBERON:0000043	85.42	gold quality
decidua	UBERON:0002450	83.72	gold quality
right lobe of liver	UBERON:0001114	83.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	1321.93
E-MTAB-10287	yes	45.00
E-CURD-119	yes	12.34
E-ANND-3	yes	6.53

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

721 targets.

Target	Regulation
AATF
ABCB1
ABCB10
ABCB11	Unknown
ABCC2	Unknown
ABCC3	Unknown
ABCG2	Unknown
ABL1
ACE2	Unknown
ACHE
ACKR3
ACP3	Unknown
ACSBG1
ADA
ADAM17
ADAM2
ADCYAP1
ADIPOQ
ADIPOR1
ADORA1	Unknown
AFMID
AGL
AGO1
AGO2
AGO3
AGO4
AGTR2	Unknown
AHR	Unknown
AICDA	Activation
AIP

JASPAR motifs

Motif	Name	Family
MA0112.1	ESR1	Steroid hormone receptors (NR3)
MA0112.2	ESR1	Steroid hormone receptors (NR3)
MA0112.3	ESR1	Steroid hormone receptors (NR3)
MA0112.4	ESR1	Steroid hormone receptors (NR3)

JASPAR matrix evidence (PMIDs): PMID:15563547, PMID:19339991

Upstream regulators (CollecTRI, top): AHR, AIP, AP1, AR, ARID5A, ARNT, ATF6, BARD1, BARX2, BRCA1, CEBPD, CREB1, DBP, DNMT1, DNMT3A, DNMT3B, E2F4, ESR1, ESR2, ESRRA, FLI1, FOS, FOSL1, FOXA1, FOXC1, FOXE1, FOXM1, FOXN1, FOXO3, FOXP1, GATA1, GATA3, HDAC1, HDAC7, HDAC9, HESX1, HIF1A, HOXA10, HOXB13, HTATIP2

miRNA regulators (miRDB)

269 targeting ESR1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-607	99.97	73.62	5593

Literature-anchored findings (GeneRIF, showing 40)

• The ligand-binding domain of estrogen receptor alpha has been expressed, purified, and crystallized to yield high amounts of soluble protein, in order to solve the structure in its native form without renaturation or modification steps. (PMID:11437591)
• ERa but not ERbeta is present in human preadipocytes (PMID:11720251)
• Association of a T262C transition in exon 1 of estrogen-receptor-alpha gene with skeletal responsiveness to estrogen in post-menopausal women. (PMID:11765043)
• To determine whether receptor-induced changes in DNA structure are related to transactivation, we compared the abilities of ER alpha and ER beta to activate transcription and induce distortion and bending in DNA. (PMID:11773069)
• Estrogen receptors are found in brain areas involved in regulation of food intake. The anorexic effects of estrogen are accentuated by stress, thus that variation in the estrogen receptors may contribute to the genetic susceptibility to AN in females. (PMID:11803451)
• Reduction of coactivator expression by antisense oligodeoxynucleotides inhibits ERalpha transcriptional activity and MCF-7 proliferation (PMID:11818499)
• mutations targeted to predicted helix in the extreme carboxyl-terminal region alter its response to estradiol and 4-hydroxytamoxifen (PMID:11823467)
• expression of estrogen receptor alpha and estrogen receptor beta were studied in leiomyomas and homologous myometrium from women in the proliferative phase of the menstrual cycle and from women treated with a gonadotropin-releasing hormone analogue (PMID:11826769)
• Estrogen receptors play a role in the activation of amino acid transport system A by estrogen. (PMID:11836633)
• patients that progressed to breast cancer showed significantly higher ER-alpha expression in their HUT (hyperplasia of usual type)foci compared with controls (PMID:11839580)
• There was strong linkage disequilibrium between the three loci and a significant sex difference was observed in allele (for (TA)(n), PvuII) and genotype (for XbaI) frequencies. (PMID:11857578)
• Results indicate a weak and transient activation of estrogen receptors by estradiol stimulation that may be enhanced by growth factors. (PMID:11867270)
• RTA, a negative coregulator for ERalpha was isolated (PMID:11875103)
• Coronary artery wall atherosclerosis in relation to the estrogen receptor 1 gene polymorphism: an autopsy study; the ESR1 gene is a potential candidate behind the pathogenesis of acute coronary events (PMID:11894143)
• role in blood pressure (PMID:11903314)
• Mutations of tyrosine 537 in the human estrogen receptor-alpha selectively alter the receptor’s affinity for estradiol and the kinetics of the interaction (PMID:11914066)
• these results show that although estrogen can up-regulate endogenous PR gene expression in osteoblasts via both ER isoforms, ER-alpha is the predominant inducer (PMID:11918216)
• Postmenopausal women with coronary disease who have the ER-alpha IVS1-401 C/C genotype, or several other closely related genotypes, have an augmented response of HDL cholesterol to hormone-replacement therapy. (PMID:11919305)
• Results show that DNA-102 produced a 36-fold increase in the level of total ER alpha mRNA and a 12-fold increase in the level of mRNA for the F isoform transcribed from the upstream F promoter, and induced a more differentiated osteoblastic phenotype. (PMID:11922631)
• the extent of AF-2-dependent cofactor recruitment by ERalpha or ERbeta is affected both by ER ligands and estrogen-responsive element sequences (PMID:11923465)
• Association of polymorphisms of the oestrogen receptor alpha gene with the age of menarche (PMID:11925413)
• Interaction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor alpha (PMID:11937504)
• crystal structures of the ER alpha ligand binding domain (LBD) bound to both THC and a fragment of the transcriptional coactivator GRIP1, and the ER beta LBD bound to THC (PMID:11953755)
• MAP kinase mediates growth factor-induced nuclear translocation of estrogen receptor alpha. (PMID:11959092)
• Identification of ten exon deleted ERbeta mRNAs in human ovary, breast, uterus and bone tissues: alternate splicing pattern of estrogen receptor beta mRNA is distinct from that of estrogen receptor alpha. (PMID:11959119)
• possesses a novel large-scale chromatin unfolding activity when tethered or recruited to DNA (PMID:11971975)
• demonstrated that ERalpha but not ERbeta directly interacts with calmodulin (PMID:11981030)
• effect on cyclin D1 expression (PMID:11986316)
• genetic variants in panic disorder (PMID:11992565)
• in addition to the alternative cis-splicing, the hER alpha gene is also subject to natural trans-splicing (PMID:12011094)
• estrogen via estrogen receptor 1 directly modulates differentiation of bipotential stromal cells into the osteoblast and adipocyte lineages, causing a lineage shift toward the osteoblast (PMID:12021200)
• contribution of genetic polymorphism of oestrogen and androgen receptor (AR) genes in male infertility (PMID:12031042)
• ADA3-containing complexes associate with estrogen receptor alpha (PMID:12034840)
• PRMT2 is a novel ERalpha coactivator. (PMID:12039952)
• review of connections and regulation of the human estrogen receptor alpha (PMID:12040178)
• tentative findings provide evidence that genetic variation in ESR1 may modify coronary reactivity and LDL oxidation and reflect differences in the early pathogenesis of coronary dysfunction in these healthy young men (PMID:12059984)
• Expression of c-erbB-2 in node negative breast cancer does not correlate with estrogen receptor status, predictors of hormone responsiveness, or PCNA expression. (PMID:12088102)
• The constitutively activated MAP kinase cascade in endometrial cancer cells enhances ERalpha transcriptional activity via the AF1 domain. This activation pathway may be involved in the stimulatory effect of tamoxifen on endometrial cancer. (PMID:12088871)
• Structural regions (BOX-1 & -2)required for the ability of ERalpha to induce transcription synergistically from tandem ERE sequences are also critical for the interaction of the receptor with the co-regulatory proteins. (PMID:12088878)
• Formation of an hER alpha-COUP-TFI complex enhances hER alpha AF-1 through Ser118 phosphorylation by MAPK. (PMID:12093745)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	esr1	ENSDARG00000004111
mus_musculus	Esr1	ENSMUSG00000019768
rattus_norvegicus	Esr1	ENSRNOG00000019358
drosophila_melanogaster	ERR	FBGN0035849

Paralogs (8): PGR (ENSG00000082175), NR3C1 (ENSG00000113580), ESRRB (ENSG00000119715), ESR2 (ENSG00000140009), NR3C2 (ENSG00000151623), AR (ENSG00000169083), ESRRA (ENSG00000173153), ESRRG (ENSG00000196482)

Protein

Protein identifiers

Estrogen receptor — P03372 (reviewed: P03372)

Alternative names: ER-alpha, Estradiol receptor, Nuclear receptor subfamily 3 group A member 1

All UniProt accessions (8): P03372, B0QYW7, G4XH65, H0Y4W6, Q5T5H8, Q9H2M1, Q9H2M2, Q9UE35

UniProt curated annotations — full annotation on UniProt →

Function. Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Maintains neuronal survival in response to ischemic reperfusion injury when in the presence of circulating estradiol (17-beta-estradiol/E2). Involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full-length receptor. Binds to ERE and inhibits isoform 1.

Subunit / interactions. Binds DNA as a homodimer. Can form a heterodimer with ESR2. Interacts with FOXC2, MAP1S, SLC30A9, UBE1C and NCOA3 coactivator. Interacts with PELP1, the interaction is enhanced by 17-beta-estradiol, the interaction increases ESR1 transcriptional activity. Interacts with EP300; the interaction is estrogen-dependent and enhanced by CITED1. Interacts with CITED1; the interaction is estrogen-dependent. Interacts with NCOA5 and NCOA6 coactivators. Interacts with NCOA7; the interaction is a ligand-inducible. Interacts with PHB2, and UBE1C. Interacts with AKAP13. Interacts with CUEDC2. Interacts with KDM5A. Interacts with SMARD1. Interacts with HEXIM1. Interacts with PBXIP1. Interaction with MUC1 is stimulated by 7 beta-estradiol (E2) and enhances ESR1-mediated transcription. Interacts with DNTTIP2, FAM120B and UIMC1. Interacts with isoform 4 of TXNRD1. Interacts with KMT2D/MLL2. Interacts with ATAD2 and this interaction is enhanced by estradiol. Interacts with KIF18A and LDB1. Interacts with RLIM (via C-terminus). Interacts with MACROD1. Interacts with SH2D4A and PLCG. Interaction with SH2D4A blocks binding to PLCG and inhibits estrogen-induced cell proliferation. Interacts with DYNLL1. Interacts with CCDC62 in the presence of estradiol/E2; this interaction seems to enhance the transcription of target genes. Interacts with NR2C1; the interaction prevents homodimerization of ESR1 and suppresses its transcriptional activity and cell growth. Interacts with DNAAF4. Interacts with PRMT2. Interacts with RBFOX2. Interacts with STK3/MST2 only in the presence of SAV1 and vice-versa. Binds to CSNK1D. Interacts with NCOA2; NCOA2 can interact with ESR1 AF-1 and AF-2 domains simultaneously and mediate their transcriptional synergy. Interacts with DDX5. Interacts with NCOA1; the interaction seems to require a self-association of N-terminal and C-terminal regions. Interacts with ZNF366, DDX17, NFKB1, RELA, SP1 and SP3. Interacts with NRIP1. Interacts with GPER1; the interaction occurs in an estrogen-dependent manner. Interacts with CLOCK and the interaction is stimulated by estrogen. Interacts with BCAS3. Interacts with TRIP4 (ufmylated); estrogen dependent. Interacts with LMTK3; the interaction phosphorylates ESR1 (in vitro) and protects it against proteasomal degradation. Interacts with CCAR2 (via N-terminus) in a ligand-independent manner. Interacts with ZFHX3. Interacts with SFR1 in a ligand-dependent and -independent manner. Interacts with DCAF13, LATS1 and DCAF1; regulates ESR1 ubiquitination and ubiquitin-mediated proteasomal degradation. Interacts (via DNA-binding domain) with POU4F2 (C-terminus); this interaction increases the estrogen receptor ESR1 transcriptional activity in a DNA- and ligand 17-beta-estradiol-independent manner. Interacts with ESRRB isoform 1. Interacts with UBE3A and WBP2. Interacts with GTF2B. Interacts with RBM39. In the absence of hormonal ligand, interacts with TACC1. Interacts with PI3KR1 or PI3KR2 and PTK2/FAK1. Interacts with SRC. Interacts with BAG1; the interaction is promoted in the absence of estradiol (17-beta-estradiol/E2). Interacts with and ubiquitinated by STUB1; the interaction is promoted in the absence of estradiol (17-beta-estradiol/E2). Interacts with NEDD8. Probably homodimerizes or heterodimerizes with isoform 1 and ESR2.

Subcellular location. Nucleus. Cytoplasm. Cell membrane Nucleus. Cell membrane. Golgi apparatus.

Tissue specificity. Widely expressed. Not expressed in the pituitary gland. Widely expressed, however not expressed in the pituitary gland.

Post-translational modifications. Phosphorylated by cyclin A/CDK2 and CK1. Phosphorylation probably enhances transcriptional activity. Self-association induces phosphorylation. Dephosphorylation at Ser-118 by PPP5C inhibits its transactivation activity. Phosphorylated by LMTK3 in vitro. Glycosylated; contains N-acetylglucosamine, probably O-linked. Ubiquitinated; regulated by LATS1 via DCAF1 it leads to ESR1 proteasomal degradation. Deubiquitinated by OTUB1. Ubiquitinated by STUB1/CHIP; in the CA1 hippocampal region following loss of endogenous circulating estradiol (17-beta-estradiol/E2). Ubiquitinated by UBR5, leading to its degradation: UBR5 specifically recognizes and binds ligand-bound ESR1 when it is not associated with coactivators (NCOAs). In presence of NCOAs, the UBR5-degron is not accessible, preventing its ubiquitination and degradation. Dimethylated by PRMT1 at Arg-260. The methylation may favor cytoplasmic localization. Demethylated by JMJD6 at Arg-260. Palmitoylated (isoform 3). Not biotinylated (isoform 3). Palmitoylated by ZDHHC7 and ZDHHC21. Palmitoylation is required for plasma membrane targeting and for rapid intracellular signaling via ERK and AKT kinases and cAMP generation, but not for signaling mediated by the nuclear hormone receptor.

Disease relevance. Estrogen resistance (ESTRR) [MIM:615363] A disorder characterized by partial or complete resistance to estrogens, in the presence of elevated estrogen serum levels. Clinical features include absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, reduced bone mineral density, osteoporosis, continued growth into adulthood and very tall adult stature. Glucose intolerance, hyperinsulinemia and lipid abnormalities may also be present. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. The modulating domain, also known as A/B or AF-1 domain has a ligand-independent transactivation function. The C-terminus contains a ligand-dependent transactivation domain, also known as E/F or AF-2 domain which overlaps with the ligand binding domain. AF-1 and AF-2 activate transcription independently and synergistically and act in a promoter- and cell-specific manner. AF-1 seems to provide the major transactivation function in differentiated cells.

Polymorphism. Genetic variations in ESR1 are correlated with bone mineral density (BMD). Low BMD is a risk factor for osteoporotic fracture. Osteoporosis is characterized by reduced bone mineral density, disruption of bone microarchitecture, and the alteration of the amount and variety of non-collagenous proteins in bone. Osteoporotic bones are more at risk of fracture.

Miscellaneous. Selective estrogen receptor modulators (SERMs), such as tamoxifen, raloxifene, toremifene, lasofoxifene, clomifene, femarelle and ormeloxifene, have tissue selective agonistic and antagonistic effects on the estrogen receptor (ER). They interfere with the ER association with coactivators or corepressors, mainly involving the AF-2 domain. Produced by alternative promoter usage. Produced by alternative splicing of isoform 3.

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

Isoforms (4)

UniProt ID	Names	Canonical?
P03372-1	1, Long, hER-alpha66, ER66	yes
P03372-2	2, Short
P03372-3	3, hER-alpha46, ER46
P03372-4	4, hER-alpha36, ER36

RefSeq proteins (12): NP_000116, NP_001116212, NP_001116213, NP_001116214, NP_001278159, NP_001278170, NP_001315029, NP_001372497, NP_001372498, NP_001372499, NP_001372500, NP_001372501 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001292	Estr_rcpt	Family
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR024178	Est_rcpt/est-rel_rcp	Family
IPR024736	Oestrogen-typ_rcpt_final_C_dom	Domain
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR046944	Estr_rcpt_N	Domain
IPR050200	Nuclear_hormone_rcpt_NR3	Family

Pfam: PF00104, PF00105, PF02159, PF12743

UniProt features (84 total): helix 18, mutagenesis site 12, region of interest 11, strand 10, sequence variant 8, modified residue 6, binding site 3, splice variant 3, turn 3, compositionally biased region 2, zinc finger region 2, chain 1, domain 1, DNA-binding region 1, lipid moiety-binding region 1, glycosylation site 1, sequence conflict 1

Structure

Experimental structures (PDB)

478 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7BAA	X-RAY DIFFRACTION	1.1
8BZC	X-RAY DIFFRACTION	1.1
8BZW	X-RAY DIFFRACTION	1.1
8C04	X-RAY DIFFRACTION	1.1
7B9R	X-RAY DIFFRACTION	1.15
7B9T	X-RAY DIFFRACTION	1.15
7NFW	X-RAY DIFFRACTION	1.19
6HMU	X-RAY DIFFRACTION	1.2
7BA8	X-RAY DIFFRACTION	1.2
8APS	X-RAY DIFFRACTION	1.2
8BX3	X-RAY DIFFRACTION	1.2
8BXI	X-RAY DIFFRACTION	1.2
8BYO	X-RAY DIFFRACTION	1.2
8BZ0	X-RAY DIFFRACTION	1.2
8BZA	X-RAY DIFFRACTION	1.25
7BAB	X-RAY DIFFRACTION	1.3
8BZ9	X-RAY DIFFRACTION	1.3
9I6S	X-RAY DIFFRACTION	1.3
9I6T	X-RAY DIFFRACTION	1.3
9I6U	X-RAY DIFFRACTION	1.3
9I6V	X-RAY DIFFRACTION	1.3
9I6W	X-RAY DIFFRACTION	1.3
9I6X	X-RAY DIFFRACTION	1.3
7NFB	X-RAY DIFFRACTION	1.33
8ARR	X-RAY DIFFRACTION	1.35
9I71	X-RAY DIFFRACTION	1.35
9I72	X-RAY DIFFRACTION	1.35
8AFN	X-RAY DIFFRACTION	1.36
7BA3	X-RAY DIFFRACTION	1.4
7BA6	X-RAY DIFFRACTION	1.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P03372-F1	67.14	0.45

Functional residue map

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

Ligand- & substrate-binding residues (3): 353; 394; 524

Post-translational modifications (7): 104, 106, 118, 167, 260, 537, 447

Glycosylation sites (1): 10

Mutagenesis-validated functional residues (12):

Position	Phenotype
39	impairs af-1 transactivation.
43	impairs af-1 transactivation.
104	loss of cyclin a-dependent induction of transcriptional activation.
106	loss of cyclin a-dependent induction of transcriptional activation.
118	decreases phosphorylation and transactivation activity. abolishes af-1 transactivation. insensitive to ppp5c inhibition
118	enhances transactivation activity. insensitive to ppp5c inhibition of transactivation activity.
260	loss of methylation.
364	has higher transcriptional activity in the absence of wild type er. inhibits transcriptional activity when coexpressed w
386	loss of transmembrane localization, no effect on peripheral membrane localization. impairs activation of estrogen-induce
447	loss of hormone binding capacity and temperature-sensitive loss in dna-binding.
537	reduces pelp1-mediated activation of transcriptional activity.
539	abolishes interaction with ncoa1, ncoa2 and ncoa3.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-383280	Nuclear Receptor transcription pathway
R-HSA-4090294	SUMOylation of intracellular receptors
R-HSA-5689896	Ovarian tumor domain proteases
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8866910	TFAP2 (AP-2) family regulates transcription of growth factors and their receptors
R-HSA-8931987	RUNX1 regulates estrogen receptor mediated transcription
R-HSA-8939211	ESR-mediated signaling
R-HSA-8939256	RUNX1 regulates transcription of genes involved in WNT signaling
R-HSA-8939902	Regulation of RUNX2 expression and activity
R-HSA-9009391	Extra-nuclear estrogen signaling
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9841251	Mitochondrial unfolded protein response (UPRmt)
R-HSA-9927418	Developmental Lineage of Mammary Gland Luminal Epithelial Cells
R-HSA-9927426	Developmental Lineage of Mammary Gland Alveolar Cells

MSigDB gene sets: 693 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GCACCTT_MIR18A_MIR18B, ELVIDGE_HYPOXIA_DN, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, MORF_FLT1, WANG_CLIM2_TARGETS_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_GLAND_MORPHOGENESIS, GOBP_REGULATION_OF_MORPHOGENESIS_OF_A_BRANCHING_STRUCTURE, PID_TELOMERASE_PATHWAY, GOBP_RESPONSE_TO_ESTRADIOL, MORF_MSH3, GOBP_PROSTATE_GLAND_MORPHOGENESIS, GOBP_INFLAMMATORY_RESPONSE

GO Biological Process (47): negative regulation of transcription by RNA polymerase II (GO:0000122), antral ovarian follicle growth (GO:0001547), epithelial cell development (GO:0002064), chromatin remodeling (GO:0006338), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), signal transduction (GO:0007165), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), positive regulation of cytosolic calcium ion concentration (GO:0007204), androgen metabolic process (GO:0008209), male gonad development (GO:0008584), negative regulation of gene expression (GO:0010629), nuclear receptor-mediated steroid hormone signaling pathway (GO:0030518), estrogen receptor signaling pathway (GO:0030520), response to estradiol (GO:0032355), regulation of toll-like receptor signaling pathway (GO:0034121), negative regulation of smooth muscle cell apoptotic process (GO:0034392), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), steroid hormone receptor signaling pathway (GO:0043401), obsolete negative regulation of DNA-binding transcription factor activity (GO:0043433), response to estrogen (GO:0043627), positive regulation of nitric oxide biosynthetic process (GO:0045429), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), fibroblast proliferation (GO:0048144), positive regulation of fibroblast proliferation (GO:0048146), stem cell differentiation (GO:0048863), regulation of inflammatory response (GO:0050727), positive regulation of nitric-oxide synthase activity (GO:0051000), obsolete positive regulation of DNA-binding transcription factor activity (GO:0051091), RNA polymerase II preinitiation complex assembly (GO:0051123), uterus development (GO:0060065), vagina development (GO:0060068), prostate epithelial cord elongation (GO:0060523), prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis (GO:0060527), regulation of branching involved in prostate gland morphogenesis (GO:0060687), mammary gland branching involved in pregnancy (GO:0060745), mammary gland alveolus development (GO:0060749), epithelial cell proliferation involved in mammary gland duct elongation (GO:0060750), protein localization to chromatin (GO:0071168)

GO Molecular Function (31): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), TFIIB-class transcription factor binding (GO:0001093), transcription coregulator binding (GO:0001221), transcription corepressor binding (GO:0001222), transcription coactivator binding (GO:0001223), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), nuclear receptor activity (GO:0004879), steroid binding (GO:0005496), calmodulin binding (GO:0005516), beta-catenin binding (GO:0008013), zinc ion binding (GO:0008270), TBP-class protein binding (GO:0017025), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), nitric-oxide synthase regulator activity (GO:0030235), nuclear estrogen receptor activity (GO:0030284), nuclear estrogen receptor binding (GO:0030331), estrogen response element binding (GO:0034056), identical protein binding (GO:0042802), ATPase binding (GO:0051117), 14-3-3 protein binding (GO:0071889), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), nuclear steroid receptor activity (GO:0003707), protein binding (GO:0005515), lipid binding (GO:0008289), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (11): chromatin (GO:0000785), euchromatin (GO:0000791), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Transcriptional regulation by RUNX1	2
ESR-mediated signaling	2
Developmental Lineages of the Mammary Gland	2
Signaling by ERBB4	1
Intracellular signaling by second messengers	1
PI3K/AKT Signaling in Cancer	1
Generic Transcription Pathway	1
SUMO E3 ligases SUMOylate target proteins	1
Deubiquitination	1
Negative regulation of the PI3K/AKT network	1
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1
Signaling by Nuclear Receptors	1
Transcriptional regulation by RUNX2	1
Cellular responses to stress	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	3
protein binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of gene expression	2
regulation of DNA-templated transcription	2
chromatin	2
transcription coregulator binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
intracellular membrane-bounded organelle	2
cytoplasm	2
negative regulation of DNA-templated transcription	1
ovarian follicle development	1
developmental process involved in reproduction	1
ovulation cycle process	1
developmental growth	1
epithelial cell differentiation	1
cell development	1
chromatin organization	1
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor signaling pathway	1
phospholipase C activator activity	1
regulation of biological quality	1
steroid metabolic process	1
hormone metabolic process	1
gonad development	1
development of primary male sexual characteristics	1
gene expression	1
negative regulation of macromolecule biosynthetic process	1
steroid hormone receptor signaling pathway	1
nuclear receptor-mediated signaling pathway	1
nuclear receptor-mediated steroid hormone signaling pathway	1
response to lipid	1

Protein interactions and networks

STRING

8546 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ESR1	NCOA3	Q9Y6Q9	997
ESR1	SRC	P12931	996
ESR1	JUN	P05412	995
ESR1	BRCA1	P38398	995
ESR1	FOS	P01100	994
ESR1	IGF1R	P08069	994
ESR1	CAV1	Q03135	992
ESR1	FOXA1	P55317	990
ESR1	NRIP1	P48552	988
ESR1	HSP90AA1	P07900	988
ESR1	NCOR1	O75376	987
ESR1	HDAC1	Q13547	987
ESR1	NCOA1	Q15788	986
ESR1	GNA13	Q14344	985
ESR1	HSP90AB1	P08238	983

IntAct

392 interactions, top by confidence:

A	B	Type	Score
ESR1	ESR1	psi-mi:“MI:0914”(association)	0.870
ESR1	SRC	psi-mi:“MI:0914”(association)	0.850
SRC	ESR1	psi-mi:“MI:0914”(association)	0.850
ESR1	NCOA1	psi-mi:“MI:0914”(association)	0.840
ESR1	BRCA1	psi-mi:“MI:0407”(direct interaction)	0.810
BRCA1	ESR1	psi-mi:“MI:0407”(direct interaction)	0.810
BRCA1	ESR1	psi-mi:“MI:0915”(physical association)	0.810
ESR1	BRCA1	psi-mi:“MI:0915”(physical association)	0.810
	ESR1	psi-mi:“MI:0914”(association)	0.790
ESR1		psi-mi:“MI:0914”(association)	0.790
PGR	ESR1	psi-mi:“MI:0915”(physical association)	0.770
ESR1	PGR	psi-mi:“MI:0403”(colocalization)	0.770
ESR1	PGR	psi-mi:“MI:0915”(physical association)	0.770

BioGRID (3444): SRC (Reconstituted Complex), SRC (Co-localization), PSMB9 (Co-localization), POLR2A (Co-localization), POLR2B (Co-localization), POLR2C (Co-localization), POLR2D (Co-localization), POLR2E (Co-localization), POLR2F (Co-localization), POLR2G (Co-localization), POLR2H (Co-localization), POLR2I (Co-localization), POLR2L (Co-localization), POLR2J (Co-localization), POLR2K (Co-localization)

ESM2 similar proteins: A0A072VIM5, A0A0K0PU92, A0JM23, A2CIR7, F4IG73, F4JD14, G3LSH3, G8GTN7, O00750, O42132, O75460, O80560, P03372, P0CI65, P50241, P50242, P57717, P57753, Q0JJ01, Q29040, Q2HW56, Q2QXZ2, Q2RAQ5, Q53AD2, Q5D0W8, Q5M9H0, Q5YLM1, Q5ZLG9, Q6AZT7, Q6KAE5, Q6NLQ8, Q6PJI9, Q6WQJ1, Q7EZ44, Q7T0L6, Q7TNH6, Q7XAP4, Q7Z494, Q8C0M0, Q8CFE5

Diamond homologs: A7X8B3, A7X8B5, A7X8B7, A7X8B9, A7X8C2, A7X8C4, A7X8C7, A7X8C9, A7X8D2, A7X8D4, A7XW16, A7XW20, A7XW25, O08537, O08580, O13012, O13186, O46567, O73673, O95718, O97775, O97776, O97952, O97960, P03372, P04150, P06186, P06211, P06212, P06401, P06536, P06537, P07812, P08235, P10275, P11474, P11475, P15207, P16058, P19091

SIGNOR signaling

141 interactions.

A	Effect	B	Mechanism
ESR1	“up-regulates quantity by expression”	NCOA2	“transcriptional regulation”
NR0B2	down-regulates	ESR1	binding
EGFR	up-regulates	ESR1	phosphorylation
ERBB2	up-regulates	ESR1	phosphorylation
PRKACA	up-regulates	ESR1	phosphorylation
ESR1	“up-regulates quantity by expression”	CCND1	“transcriptional regulation”
MAPK14	up-regulates	ESR1	phosphorylation
GSK3B	up-regulates	ESR1	phosphorylation
ESR1	“down-regulates quantity by repression”	PPARG	“transcriptional regulation”
ESR1	up-regulates	PIK3R1	binding
ESR1	up-regulates	PIK3R2	binding
KMT2D	up-regulates	ESR1	binding
“MLL2 complex”	up-regulates	ESR1	binding
17beta-estradiol	up-regulates	ESR1	“chemical activation”
MAPK1	up-regulates	ESR1	phosphorylation
MAPK3	up-regulates	ESR1	phosphorylation
IKBKE	up-regulates	ESR1	phosphorylation
CSNK2A1	down-regulates	ESR1	phosphorylation
ABL1	up-regulates	ESR1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 68 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
Nuclear Receptor transcription pathway	5	20.0×	5e-04
ESR-mediated signaling	7	18.0×	5e-05
SUMOylation	5	16.3×	1e-03
PPARA activates gene expression	7	13.2×	1e-04
Transcriptional regulation of white adipocyte differentiation	5	13.0×	2e-03
Estrogen-dependent gene expression	8	12.1×	6e-05
Signaling by Nuclear Receptors	5	10.2×	4e-03
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	6	9.9×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of apoptotic process	9	5.0×	5e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

ESR1 has been a focus in breast cancer for quite some time, but is also clinically relevant in endometrial, ovarian and other cancer types. The identification of ER-positive breast cancers that are resistant to hormone therapy have inspired clinical sequencing efforts to shed light on the mechanisms of this resistance. A number of mutations in the ligand binding domain of ESR1 have been implicated in hormone resistance and anti-estrogen therapies. These observations have spurred efforts to develop therapeutics that stimulate ESR1 protein degradation (e.g. Fulvestrant), rather than acting as a small molecule antagonist. These agents are currently in clinical trials and have seen some success.

From intOGen — cancer-driver classification: activating (oncogene-like) across 4 cancer types — BRCA, LUSC, MEL, UCEC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	0
Uncertain significance	78
Likely benign	60
Benign	46

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
16590	NM_000125.4(ESR1):c.1339_1340delinsGC (p.Cys447Ala)	Pathogenic
16592	NM_000125.4(ESR1):c.469C>T (p.Arg157Ter)	Pathogenic
3899918	NM_000125.4(ESR1):c.453-351A>G	Pathogenic
538429	NC_000006.12:g.(?152122416)(153426916_?)del	Pathogenic
60557	NM_000125.4(ESR1):c.1125G>T (p.Gln375His)	Pathogenic

SpliceAI

4481 predictions. Top by Δscore:

Variant	Effect	Δscore
6:151690665:G:GG	donor_gain	1.0000
6:151842595:A:AG	acceptor_gain	1.0000
6:151842595:AG:A	acceptor_gain	1.0000
6:151842596:G:GA	acceptor_gain	1.0000
6:151842596:GG:G	acceptor_gain	1.0000
6:151842596:GGC:G	acceptor_gain	1.0000
6:151842596:GGCC:G	acceptor_gain	1.0000
6:151842596:GGCCA:G	acceptor_gain	1.0000
6:151842776:G:GT	donor_gain	1.0000
6:151842784:CAAGG:C	donor_loss	1.0000
6:151842785:AAGG:A	donor_loss	1.0000
6:151842787:GGTAA:G	donor_loss	1.0000
6:151842788:G:T	donor_loss	1.0000
6:151842789:T:G	donor_loss	1.0000
6:151880649:TAATA:T	acceptor_loss	1.0000
6:151880651:ATAGG:A	acceptor_loss	1.0000
6:151880652:TA:T	acceptor_loss	1.0000
6:151880653:AGGA:A	acceptor_loss	1.0000
6:151880769:GTG:G	donor_gain	1.0000
6:151944171:A:AG	acceptor_gain	1.0000
6:151944171:AG:A	acceptor_gain	1.0000
6:151944171:AGG:A	acceptor_gain	1.0000
6:151944172:G:GG	acceptor_gain	1.0000
6:151944172:GG:G	acceptor_gain	1.0000
6:151944172:GGG:G	acceptor_gain	1.0000
6:151944506:CAGGT:C	donor_loss	1.0000
6:151944508:GGTA:G	donor_loss	1.0000
6:151944509:G:A	donor_loss	1.0000
6:151944510:T:A	donor_loss	1.0000
6:152011759:G:T	donor_gain	1.0000

AlphaMissense

3910 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:151842697:T:A	C185S	1.000
6:151842697:T:C	C185R	1.000
6:151842697:T:G	C185G	1.000
6:151842698:G:A	C185Y	1.000
6:151842698:G:C	C185S	1.000
6:151842698:G:T	C185F	1.000
6:151842699:T:G	C185W	1.000
6:151842704:T:A	V187E	1.000
6:151842706:T:A	C188S	1.000
6:151842706:T:C	C188R	1.000
6:151842707:G:A	C188Y	1.000
6:151842707:G:C	C188S	1.000
6:151842707:G:T	C188F	1.000
6:151842708:C:G	C188W	1.000
6:151842712:G:C	D190H	1.000
6:151842713:A:C	D190A	1.000
6:151842713:A:G	D190G	1.000
6:151842713:A:T	D190V	1.000
6:151842719:C:A	A192D	1.000
6:151842724:G:C	G194R	1.000
6:151842725:G:A	G194D	1.000
6:151842725:G:T	G194V	1.000
6:151842727:T:G	Y195D	1.000
6:151842730:C:A	H196N	1.000
6:151842730:C:G	H196D	1.000
6:151842731:A:G	H196R	1.000
6:151842731:A:T	H196L	1.000
6:151842732:T:A	H196Q	1.000
6:151842732:T:G	H196Q	1.000
6:151842733:T:C	Y197H	1.000

dbSNP variants (sampled 300 via entrez): RS1000000747 (6:151741055 G>T), RS1000004850 (6:151702178 A>G), RS1000010720 (6:151966978 T>G), RS1000013375 (6:151837879 T>C), RS1000029833 (6:151790761 C>A), RS1000032314 (6:151937188 A>G), RS1000036508 (6:152003904 G>A), RS1000063282 (6:151967293 C>A,T), RS1000073376 (6:151700713 T>C), RS1000073701 (6:151924896 T>C), RS1000075189 (6:152052410 G>A), RS1000082288 (6:151795010 G>C), RS1000086295 (6:151836443 A>G,T), RS1000086754 (6:151879865 C>T), RS1000096334 (6:151683870 T>A)

Disease associations

OMIM: gene MIM:133430 | disease phenotypes: MIM:610743, MIM:612998, MIM:157300, MIM:608446, MIM:615363, MIM:114480, MIM:181800

GenCC curated gene-disease

Disease	Classification	Inheritance
estrogen resistance syndrome	Strong	Autosomal recessive

Mondo (8): autosomal recessive ataxia, Beauce type (MONDO:0012549), Emery-Dreifuss muscular dystrophy 4, autosomal dominant (MONDO:0013071), migraine with or without aura, susceptibility to, 1 (MONDO:0008000), myocardial infarction, susceptibility to (MONDO:0012039), estrogen resistance syndrome (MONDO:0014148), hereditary breast carcinoma (MONDO:0016419), migraine with or without aura, susceptibility to (MONDO:0100246), scoliosis, isolated, susceptibility to, 1 (MONDO:0008419)

Orphanet (5): Emery-Dreifuss muscular dystrophy (Orphanet:261), Autosomal recessive ataxia, Beauce type (Orphanet:88644), Hereditary breast cancer (Orphanet:227535), Estrogen resistance syndrome (Orphanet:785), Rare genetic intellectual disability (Orphanet:183757)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000098	Tall stature
HP:0000147	Polycystic ovaries
HP:0000613	Photophobia
HP:0000786	Primary amenorrhea
HP:0000823	Delayed puberty
HP:0000834	Abnormality of the adrenal glands
HP:0000837	Increased circulating gonadotropin level
HP:0000842	Hyperinsulinemia
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000956	Acanthosis nigricans
HP:0001061	Acne
HP:0001442	Typified by somatic mosaicism
HP:0001548	Overgrowth
HP:0001677	Coronary artery atherosclerosis
HP:0001952	Glucose intolerance
HP:0002013	Vomiting
HP:0002018	Nausea
HP:0002077	Migraine with aura
HP:0002083	Migraine without aura
HP:0002183	Phonophobia
HP:0002574	Episodic abdominal pain
HP:0002663	Delayed epiphyseal ossification
HP:0002750	Delayed skeletal maturation
HP:0003002	Breast carcinoma
HP:0003117	Abnormal circulating hormone concentration
HP:0003187	Breast hypoplasia

GWAS associations

126 associations (top):

Study	Trait	p-value
GCST000180_2	Bone mineral density (spine)	2.000000e-11
GCST000180_7	Bone mineral density (spine)	4.000000e-11
GCST000180_8	Bone mineral density (spine)	2.000000e-08
GCST000181_5	Bone mineral density (hip)	2.000000e-07
GCST000181_6	Bone mineral density (hip)	5.000000e-09
GCST000295_1	Bone mineral density (spine)	2.000000e-10
GCST000297_5	Bone mineral density (hip)	4.000000e-10
GCST000343_1	Breast cancer	2.000000e-15
GCST000432_5	Alcohol dependence	8.000000e-06
GCST000494_9	Bone mineral density (spine)	6.000000e-11
GCST000495_11	Bone mineral density (hip)	2.000000e-10
GCST000678_11	Breast cancer	3.000000e-06
GCST000817_80	Height	1.000000e-17
GCST000952_5	Breast cancer	1.000000e-07
GCST001063_1	Chronic myeloid leukemia	2.000000e-06
GCST001099_9	Sudden cardiac arrest	7.000000e-10
GCST001420_2	Breast cancer	2.000000e-06
GCST001585_22	Breast size	6.000000e-11
GCST001762_275	Obesity-related traits	3.000000e-06
GCST001870_5	Bone mineral density	1.000000e-09
GCST001930_3	Breast cancer	5.000000e-16
GCST001937_34	Breast cancer	2.000000e-21
GCST001956_79	Height	4.000000e-10
GCST002305_3	Breast cancer (estrogen-receptor negative, progesterone-receptor negative, and human epidermal growth factor-receptor negative)	9.000000e-06
GCST002333_10	Bone properties (heel)	7.000000e-15
GCST002333_3	Bone properties (heel)	3.000000e-18
GCST002335_1	Bone properties (heel)	3.000000e-09
GCST002335_7	Bone properties (heel)	2.000000e-10
GCST002541_58	Menarche (age at onset)	1.000000e-09
GCST002647_62	Height	8.000000e-24

EFO canonical traits (30, from GWAS)

EFO ID	Trait name
EFO:0004278	sudden cardiac arrest
EFO:0003940	physical activity
EFO:0005654	velocity of sound measurement
EFO:0004514	bone quantitative ultrasound measurement
EFO:0004703	age at menarche
EFO:0005941	mammographic density measurement
EFO:0006503	dense area measurement
EFO:0007701	spine bone mineral density
EFO:0007785	femoral neck bone mineral density
EFO:0006527	smoking status measurement
EFO:0009101	age at first birth measurement
EFO:0005763	pulse pressure measurement
EFO:0008111	diet measurement
EFO:0008307	tuberculin skin test reactivity measurement
EFO:0008322	decreased susceptibility to bacterial infection
EFO:0004344	birth weight
EFO:0009270	heel bone mineral density
EFO:0009443	BRCAX breast cancer
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0004341	body fat distribution
EFO:0009749	age at first sexual intercourse measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0005939	parental genotype effect measurement
EFO:0009863	anxiety measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004750	interleukin 10 measurement
EFO:0600067	mastiha supplement exposure measurement
EFO:0004980	appendicular lean mass
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C562840	Breast Cancer, Familial (supp.)
C567831	Emery-Dreifuss Muscular Dystrophy 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (9): CHEMBL206 (SINGLE PROTEIN), CHEMBL2093866 (PROTEIN FAMILY), CHEMBL3885521 (PROTEIN COMPLEX), CHEMBL4523681 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523713 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523721 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523726 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523754 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193788 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

162 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 367,334 (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
CHEMBL1014	CANDESARTAN CILEXETIL	4	11,194
CHEMBL1018	DIENESTROL	4	5,607
CHEMBL1023	BEXAROTENE	4	40,951
CHEMBL1076903	VARENICLINE	4	5,807
CHEMBL1085	ACETOPHENAZINE	4	5,134
CHEMBL1112	ARIPIPRAZOLE	4	24,205
CHEMBL1116	RALOXIFENE HYDROCHLORIDE	4	28,574
CHEMBL1162	NORETHINDRONE	4	91,150
CHEMBL119	TRIMETREXATE	4	57,002
CHEMBL1200430	ESTRADIOL ACETATE	4	1,114
CHEMBL1200623	ETHYLESTRENOL	4	1,795
CHEMBL1200624	ETHYNODIOL DIACETATE	4	5,941
CHEMBL1200761	CHLOROTRIANISENE	4	23,246
CHEMBL1200973	ESTRADIOL CYPIONATE	4	4,089
CHEMBL1201151	MESTRANOL	4	10,339
CHEMBL1201165	QUINESTROL	4	3,365
CHEMBL1201794	RIBOFLAVIN 5’-PHOSPHATE	4	7,348
CHEMBL1230314	ESTETROL ANHYDROUS	4	1,198
CHEMBL1231	OXYBUTYNIN	4	15,072
CHEMBL125	MILTEFOSINE	4	24,203
CHEMBL1276308	MIFEPRISTONE	4
CHEMBL1289601	LENVATINIB	4
CHEMBL1292	CLOFAZIMINE	4
CHEMBL1295	BUTOCONAZOLE	4
CHEMBL1329455	MOLSIDOMINE	4
CHEMBL135	ESTRADIOL	4
CHEMBL1358	FULVESTRANT	4
CHEMBL1359	ERTAPENEM	4
CHEMBL1382	TOLTERODINE	4
CHEMBL1387	NORETHYNODREL	4

Clinical evidence (CIViC)

Drug × variant × indication: 29 predictive associations from 31 curated evidence items; also 2 functional.

Variant	Therapy	Indication	Effect	Level	CIViC
ESR1 D538G	Elacestrant	Estrogen-receptor Positive Breast Cancer	Sensitivity/Response	CIViC A	EID12219
ESR1 L536Q	Elacestrant	Estrogen-receptor Positive Breast Cancer	Sensitivity/Response	CIViC A	EID12229
ESR1 Mutation	Elacestrant	Breast Cancer	Sensitivity/Response	CIViC A	EID11443
ESR1 Mutation	Imlunestrant Regimen + Abemaciclib Regimen	Breast Carcinoma	Sensitivity/Response	CIViC A	EID12599
ESR1 Mutation	Aromatase Inhibitor + Fulvestrant + Imlunestrant Regimen	Breast Carcinoma	Sensitivity/Response	CIViC A	EID12600
ESR1 S463P	Elacestrant	Estrogen-receptor Positive Breast Cancer	Sensitivity/Response	CIViC A	EID12230
ESR1 Y537C	Elacestrant	Estrogen-receptor Positive Breast Cancer	Sensitivity/Response	CIViC A	EID12222
ESR1 Y537N	Elacestrant	Estrogen-receptor Positive Breast Cancer	Sensitivity/Response	CIViC A	EID12221
ESR1 Y537S	Elacestrant	Estrogen-receptor Positive Breast Cancer	Sensitivity/Response	CIViC A	EID12220
ESR1 Y537N	Palbociclib	Breast Cancer	Sensitivity/Response	CIViC B	EID4817 +1
ESR1 Y537S	Palbociclib	Breast Cancer	Sensitivity/Response	CIViC B	EID4819 +1
ESR1 Overexpression	Palbociclib + Letrozole	Breast Cancer	Sensitivity/Response	CIViC B	EID1541
ESR1 Y537S	Selective Estrogen Receptor Covalent Antagonist H3B-6545	Breast Carcinoma	Sensitivity/Response	CIViC B	EID12616
PIK3CA Mutation OR RB1 Mutation OR ESR1 Mutation	Fulvestrant + Palbociclib	Breast Cancer	Resistance	CIViC B	EID12045
ESR1 D538G	Palbociclib	Breast Cancer	Sensitivity/Response	CIViC C	EID4813
ESR1 D538G	Letrozole + Palbociclib	Breast Cancer	Sensitivity/Response	CIViC C	EID4814
ESR1 S463P	Palbociclib	Breast Cancer	Sensitivity/Response	CIViC C	EID4815
ESR1 Y537C	Palbociclib	Breast Cancer	Sensitivity/Response	CIViC C	EID4812
ESR1 D538G	Fulvestrant + Tamoxifen	Breast Cancer	Sensitivity/Response	CIViC D	EID291
ESR1 L536Q	Tamoxifen + Fulvestrant	Breast Cancer	Sensitivity/Response	CIViC D	EID290
ESR1 Y537C	Tamoxifen + Fulvestrant	Breast Cancer	Sensitivity/Response	CIViC D	EID292
ESR1 Y537N	Fulvestrant + Tamoxifen	Breast Cancer	Sensitivity/Response	CIViC D	EID293
ESR1 Y537S	Fulvestrant + Tamoxifen	Breast Cancer	Sensitivity/Response	CIViC D	EID294
ESR1 D538G	Hormone Therapy	Breast Cancer	Resistance	CIViC D	EID243
ESR1 L536Q	Hormone Therapy	Breast Cancer	Resistance	CIViC D	EID242
ESR1 S463P	Aromatase Inhibitor	Estrogen-receptor Positive Breast Cancer	Resistance	CIViC D	EID1727
ESR1 Y537C	Hormone Therapy	Breast Cancer	Resistance	CIViC D	EID244
ESR1 Y537N	Hormone Therapy	Breast Cancer	Resistance	CIViC D	EID245
ESR1 Y537S	Hormone Therapy	Breast Cancer	Resistance	CIViC D	EID246

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

PharmGKB clinical annotations

12 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11543791	Efficacy	3	raloxifene	Menopause;Schizophrenia
rs2207396	Toxicity	3	Alkylating Agents;cisplatin	Neoplasms
rs2234693	Toxicity	3	anastrozole;letrozole	Neoplasms
rs2234693	Efficacy	3	leflunomide	Rheumatoid arthritis
rs2234693	Toxicity	3	methamphetamine	Psychotic Disorder
rs2813543	Toxicity	3	exemestane	Breast Neoplasms
rs4870061	Toxicity	3	letrozole	Breast Neoplasms
rs9322335	Toxicity	3	exemestane;letrozole	Breast Neoplasms
rs9340799	Toxicity	3	tamoxifen
rs9340799	Efficacy	3	leflunomide	Rheumatoid arthritis
rs9340799	Efficacy	3	conjugated estrogens;medroxyprogesterone
rs9340799	Toxicity	3	anastrozole;letrozole	Neoplasms

PharmGKB variants

13 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1801132	ESR1		0.00	0
rs2077647	ESR1		0.00	0
rs2207396	ESR1	3	2.50	1	Alkylating Agents;cisplatin
rs2228480	ESR1		0.00	0
rs2234693	ESR1	3	2.75	3	methamphetamine;anastrozole;letrozole;leflunomide
rs2813543	ESR1	3	2.50	1	exemestane
rs3020314	ESR1		0.00	0
rs3798577	ESR1		0.00	0
rs4870061	ESR1	3	5.00	1	letrozole
rs9322335	ESR1	3	5.00	1	exemestane;letrozole
rs9322336	ESR1		0.00	0
rs9340799	ESR1	3	2.75	4	tamoxifen;leflunomide;conjugated estrogens;medroxyprogesterone;anastrozole;letrozole
rs4986936	ESR1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: nhr — 3A. Estrogen receptors

Most potent curated ligand interactions (32 total), top 25:

Ligand	Action	Affinity	Parameter
diethylstilbestrol	Agonist	10.4	pKi
giredestrant	Antagonist	10.3	pIC50
hexestrol	Antagonist	10.3	pKi
4-hydroxytamoxifen	Agonist	9.85	pKi
17β-estradiol	Agonist	9.82	pKi
camizestrant	Antagonist	9.8	pIC50
propylpyrazoletriol	Agonist	9.64	pKi
LSZ102	Antagonist	9.52	pIC50
imlunestrant	Antagonist	9.51	pKi
raloxifene	Agonist	9.5	pKi
16α-hydroxyestrone	Agonist	9.15	pKd
fulvestrant	Antagonist	8.98	pKi
clomiphene	Antagonist	8.89	pKi
compound 5 [PMID: 40393772]	Antagonist	8.8	pIC50
ethinylestradiol	Agonist	8.7	pIC50
estriol	Agonist	8.67	pKi
methyl-piperidino-pyrazole	Antagonist	8.57	pKi
lasofoxifene	Partial agonist	8.51	pIC50
estrone	Agonist	8.5	pKi
tibolone	Agonist	8.4	pEC50
R,R-THC	Agonist	8.38	pKi
compound 17b [PMID: 35286086]	Antagonist	8.34	pIC50
tamoxifen	Agonist	7.82	pKi
norendoxifen	Antagonist	7.77	pEC50
bazedoxifene	Antagonist	7.64	pIC50

Binding affinities (BindingDB)

1971 measured of 2154 human assays (2201 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-cyclohexyl-3-(1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole	EC50	0.00114 nM
2-[(2,5-dimethoxybenzylidene)amino]-4,5-bis(2-furyl)-3-furonitrile	EC50	0.00197 nM
5-[[[1-(4-fluorophenyl)-4-keto-2H-pyrazolo[3,4-d]pyrimidin-6-yl]thio]methyl]furan-2-carboxylic acid methyl ester	EC50	0.00249 nM
3-((1R,3R)-1-(2,6-difluoro-4- (2-(3-(fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-3- methyl-1,3,4,9-tetrahydro- 2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol	EC50	0.01 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(R)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3- yl)amino)phenyl)-7-fluoro-3- methyl-3,4-dihydro-1H- pyrido[3,4-b]indol-2(9H)-yl)- 2-fluoro-2-methylpropan-1-ol	EC50	0.018 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(S)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3- yl)amino)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro- 2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol	EC50	0.021 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(R)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3- yl)amino)phenyl)-5-fluoro-3- methyl-3,4-dihydro-1H- pyrido[3,4-b]indol-2(9H)-yl)- 2-fluoro-2-methylpropan-1-ol	EC50	0.023 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(8R,9S,14S,17R)-17-ethynyl-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3,17-diol	KI	0.025 nM	US-9561238: Pharmaceutical compositions comprising estetrol derivatives for use in cancer therapy
3-fluoro-N-[2-[3- (fluoromethyl)azetidin-1- yl]ethyl]-4-[(1R,3R)-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol- 1-yl]aniline	EC50	0.025 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(S)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3- yl)amino)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4- b]indol-2(9H)-yl)-2-fluoro-2- (hydroxymethyl) propanenitrile	EC50	0.026 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
US10399939, Example 132	EC50	0.029 nM	US-10399939: Tetrahydronaphthalene estrogen receptor modulators and uses thereof
(1R,3R)-1-[4-[1-(3,3- dimethoxypropyl)azetidin-3- yl]oxy-2,6-difluoro-phenyl]- 2-(2-fluoro-2-methyl-propyl)- 3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole	EC50	0.031 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(R)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1- yl)ethoxy)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4- b]indol-2(9H)-yl)-2- (fluoromethyl)propan-1-ol	EC50	0.032 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(S)-3-((1R,3R)-1-(2,6- difluoro-4-((2-(3- (fluoromethyl)azetidin-1- yl)ethyl)amino)phenyl)-3- methyl-1,3,4,9-tetrahydro- 2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol	EC50	0.033 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(R)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3- yl)amino)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4- b]indol-2(9H)-yl)-2-fluoro-2- (hydroxymethyl) propanenitrile	EC50	0.033 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
US10399939, Example 120	EC50	0.036 nM	US-10399939: Tetrahydronaphthalene estrogen receptor modulators and uses thereof
(4-methylbenzyl)-(tetrazolo[1,5-a]quinoxalin-4-yl)amine	EC50	0.0362 nM
US10399939, Example 124	EC50	0.037 nM	US-10399939: Tetrahydronaphthalene estrogen receptor modulators and uses thereof
US10399939, Example 134	EC50	0.038 nM	US-10399939: Tetrahydronaphthalene estrogen receptor modulators and uses thereof
US10399939, Example 105	EC50	0.04 nM	US-10399939: Tetrahydronaphthalene estrogen receptor modulators and uses thereof
(1R,3R)-1-[2,6-difluoro-4-(1- methylazetidin-3-yl)oxy- phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole	EC50	0.041 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
1-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1- yl)ethoxy)phenyl)-3- methyl-3,4-dihydro-1H- pyrido[3,4-b]indol-2(9H)- yl)-2-fluoro-2- methylpropan-1-one	EC50	0.043 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
US10399939, Example 127	EC50	0.046 nM	US-10399939: Tetrahydronaphthalene estrogen receptor modulators and uses thereof
(1R,3R)-2-(2,2- difluoroethyl)-1-[2,6- difluoro-4-[1-(3- fluoropropyl)azetidin-3- yl]oxy-phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indole	EC50	0.048 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
3-(5S,7R)-5-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)-2,2-difluoropropan-1-ol 5	IC50	0.05 nM	US-12428428: Tricyclic tetrahydroisoquinoline derivative, preparation method therefor and application thereof in medicine
(1R,3R)-1-[4-(1- ethylazetidin-3-yl)oxy-2,6- difluoro-phenyl]-2-(2-fluoro- 2-methyl-propyl)-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indole	EC50	0.053 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(R)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3- yl)amino)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)-2- fluoro-2-methylpropan-1-ol	EC50	0.053 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(R)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1- yl)ethoxy)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4- b]indol-2(9H)-yl)-2- fluoropropan-1-ol	EC50	0.053 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(1R,3R)-2-(2-fluoro-2- methylpropyl)-1-(2- fluoro-4-(2-(3- (fluoromethyl)azetidin-1- yl)ethoxy)phenyl)-3- methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4- b]indole	EC50	0.056 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(1R,3R)-2-(2-fluoro-2- methylpropyl)-1-(2-fluoro-4- (2-(3-(fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-3- methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole	EC50	0.056 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
N-(4-((1R,3R)-2-(2,2- difluoroethyl)-6-fluoro-3- methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indol-1-yl)- 3,5-difluorophenyl)-1-(3- fluoropropyl)azetidin-3- amine	EC50	0.056 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
N-[4-[(1R,3R)-2-(2,2- difluoroethyl)-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indol-1-yl]-3,5-difluoro- phenyl]-1-(3- fluoropropyl)azetidin-3- amine	EC50	0.065 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(1R,3R)-1-[2,6-difluoro-4-[1- [2-(oxetan-3- yl)ethyl]azetidin-3-yl]oxy- phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole	EC50	0.066 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
2-fluoro-1-[(1R,3R)-1-[2- fluoro-4-[2-[3- (fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indol-2-yl]-2-methyl- propan-1-one	EC50	0.068 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(S)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol	IC50	0.07 nM	US-10227334: Estrogen receptor modulators and uses thereof
(1R,3R)-1-(2,6-difluoro-4-(1- (3-fluoropropyl)azetidin-3- yloxy)phenyl)-2-((3- fluorooxetan-3-yl)methyl)-3- methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole	EC50	0.07 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
2,2-Difluoro-3-((5R,7R)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propan-1-ol 18	IC50	0.07 nM	US-12428428: Tricyclic tetrahydroisoquinoline derivative, preparation method therefor and application thereof in medicine
2,2-Difluoro-3-((5R,7R)-5-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-7-methyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl-2,2-th)propan-1-ol 19	IC50	0.07 nM	US-12428428: Tricyclic tetrahydroisoquinoline derivative, preparation method therefor and application thereof in medicine
3-[(1R,3R)-1-[2,6-difluoro-4- [1-(3-fluoropropyl)azetidin-3- yl]oxy-phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indol-2-yl]-2,2-dimethyl- propanenitrile	EC50	0.072 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(1R,3R)-1-(2,6-difluoro-4-((1- (3-fluoropropyl)azetidin-3- yl)oxy)phenyl)-2-(2,2- difluoroethyl)-6-fluoro-3- methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole	EC50	0.074 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(1R,3R)-1-[2,6-difluoro-4-[1- (oxetan-3-yl)azetidin-3- yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indole	EC50	0.077 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(1R,3R)-1-[2,6-difluoro-4-[3- [3-(fluoromethyl)azetidin-1- yl]propoxy]phenyl]-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole	EC50	0.078 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(1R,3S)-1-(2,6-difluoro-4-((1- (3-fluoropropyl)azetidin-3- yl)oxy)phenyl)-2-(2-fluoro-2- methylpropyl)-3- (fluoromethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4- b]indole	EC50	0.088 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(1R,3R)-1-[2,6-difluoro-4- [(2S)-2-pyrrolidin-1- ylpropoxy]phenyl]-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole	EC50	0.09 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(1R,3R)-1-[2,6-difluoro-4-[1- (3-fluoropropyl)azetidin-3- yl]oxy-phenyl]-3-methyl-2- (2,2,2-trifluoroethyl)-1,3,4,9- tetrahydropyrido[3,4-b]indole	EC50	0.09 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(R)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3- yl)amino)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro- 2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol	EC50	0.094 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
N-(3,5-difluoro-4-((1R,3R)-2- (2-fluoro-2-methylpropyl)-3- methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indol-1- yl)phenyl)-1-(3- fluoropropyl)azetidin-3- amine	EC50	0.096 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
(1R,3S)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-3- (fluoromethyl)-2-(2-fluoro-2- methyl-propyl)-1,3,4,9- tetrahydropyrido[3,4-b]indole	EC50	0.097 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
US10399939, Example 114	EC50	0.1 nM	US-10399939: Tetrahydronaphthalene estrogen receptor modulators and uses thereof
(1R,3R)-1-[2,6-difluoro-4-[1- (3-fluoropropyl)azetidin-3- yl]oxy-phenyl]-3-methyl-2- methylsulfonyl-1,3,4,9- tetrahydropyrido[3,4-b]indole	EC50	0.1 nM	US-20250114338: TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.34	ED50	0.00456	nM	ESTRADIOL
11.00	EC50	0.01	nM	ESTRADIOL
11.00	IC50	0.01	nM	CHEMBL4591338
11.00	IC50	0.01	nM	ESTRADIOL
10.85	EC50	0.014	nM	CHEMBL5177342
10.82	Ki	0.015	nM	ACOLBIFENE
10.82	EC50	0.015	nM	CHEMBL149791
10.80	Ki	0.016	nM	CHEMBL308234
10.74	EC50	0.018	nM	ESTRADIOL
10.72	EC50	0.019	nM	ESTRADIOL
10.70	EC50	0.02	nM	ESTRADIOL
10.68	IC50	0.021	nM	CHEMBL4439408
10.64	Ki	0.023	nM	CHEMBL308234
10.62	IC50	0.024	nM	CHEMBL4439408
10.55	Ki	0.028	nM	CHEMBL291808
10.55	EC50	0.028	nM	ESTROGEN
10.54	EC50	0.029	nM	CHEMBL5787193
10.52	EC50	0.0301	nM	ESTRADIOL
10.52	Ki	0.03	nM	RALOXIFENE
10.52	EC50	0.03	nM	ESTRADIOL
10.52	IC50	0.03	nM	CHEMBL4447340
10.52	IC50	0.03	nM	CHEMBL4441471
10.51	IC50	0.031	nM	CHEMBL4649161
10.50	IC50	0.03162	nM	CHEMBL5400637
10.47	IC50	0.034	nM	CHEMBL5400637
10.44	EC50	0.036	nM	CHEMBL5756797
10.43	EC50	0.037	nM	CHEMBL5959890
10.42	EC50	0.038	nM	CHEMBL5948183
10.40	Ki	0.04	nM	CHEMBL2137046
10.40	IC50	0.04	nM	CHEMBL4518283
10.40	IC50	0.03981	nM	CHEMBL4743256
10.40	EC50	0.04	nM	CHEMBL5869147
10.38	Ki	0.042	nM	ACOLBIFENE
10.38	IC50	0.042	nM	CHEMBL5978181
10.35	IC50	0.045	nM	CHEMBL4464224
10.35	IC50	0.045	nM	CHEMBL5849595
10.34	IC50	0.046	nM	CHEMBL1193539
10.34	EC50	0.046	nM	CHEMBL5822315
10.34	EC50	0.046	nM	ESTRADIOL
10.33	Ki	0.047	nM	ACOLBIFENE
10.33	EC50	0.047	nM	ESTRADIOL
10.32	IC50	0.048	nM	CHEMBL4777139
10.30	IC50	0.05	nM	CHEMBL537254
10.30	IC50	0.05	nM	CHEMBL4455953
10.30	IC50	0.05012	nM	CHEMBL4777139
10.30	IC50	0.05	nM	GIREDESTRANT
10.30	IC50	0.05	nM	CHEMBL6009034
10.29	IC50	0.051	nM	CHEMBL4449709
10.28	IC50	0.053	nM	CHEMBL4649161
10.26	IC50	0.055	nM	CHEMBL4437985

PubChem BioAssay actives

2173 with measured affinity, of 6100 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
[2-(4-chlorophenyl)-6-hydroxy-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone	1500307: Displacement of [3H]17beta-estradiol from ER in human MCF7 cells after 18 hrs by microbeta scintillation counting method	ic50	<0.0001	uM
[4-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone	1500307: Displacement of [3H]17beta-estradiol from ER in human MCF7 cells after 18 hrs by microbeta scintillation counting method	ic50	<0.0001	uM
(2S)-5-chloro-2-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-(4-fluorophenyl)-4-methyl-2H-chromen-6-ol	1591918: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by FITC/Hoechst 33342 staining based immunofluorescence imaging analysis	ic50	<0.0001	uM
(2S)-4-chloro-2-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-(3-hydroxyphenyl)-2H-chromen-6-ol	1591918: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by FITC/Hoechst 33342 staining based immunofluorescence imaging analysis	ic50	<0.0001	uM
(1R,3R)-1-[2,6-difluoro-4-[1-(3-fluoropropyl)azetidin-3-yl]oxyphenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole	1658829: Induction of ERalpha degradation in human T47D cells	ic50	<0.0001	uM
19-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8,18-dioxatetracyclo[9.8.0.02,7.012,17]nonadeca-1(11),2(7),3,5,12(17),13,15-heptaene-5,15-diol	1624901: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by Alexafluor-488 conjugate anti-mouse IgG antibody/Hoechst 33342 staining based immunofluorescence imaging analysis	ic50	<0.0001	uM
N-[4-[(6S,8R)-7-(2,2-difluoropropyl)-8-methyl-3,6,8,9-tetrahydropyrazolo[4,5-f]isoquinolin-6-yl]-3-methoxyphenyl]-1-(3-fluoropropyl)azetidin-3-amine	1681503: Induction of ERalpha degradation in human MCF7 cells assessed as decrease in ER-alpha level incubated for 18 to 24 hrs by Alexa fluor 488/Hoechst staining based immunofluorescence imaging analysis	ic50	<0.0001	uM
2,2-difluoro-3-[(1R,3R)-1-[6-fluoro-3-[2-(3-fluoropropylamino)ethoxy]-2-methylphenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]propan-1-ol	2027451: Induction of ERalpha degradation in human MCF7 cells assessed as downregulation of ERaplha by multiplexed assay	ic50	<0.0001	uM
4-[1,1-bis(4-hydroxyphenyl)but-1-en-2-yl]phenol	1152694: Agonist activity at ER in human MCF7:WS8 cells assessed as increase in cell growth by measuring DNA level after 7 days by fluorescence analysis	ec50	0.0001	uM
Fulvestrant	1251781: Antagonist activity at ERalpha receptor in human MCF7 cells	ic50	0.0001	uM
(2R,3R,4S)-5-fluoro-3-(4-hydroxyphenyl)-4-methyl-2-[4-[(2S)-2-[(2R)-2-methylpyrrolidin-1-yl]propoxy]phenyl]-3,4-dihydro-2H-chromen-6-ol	248124: Inhibition of estrogen dependent human MCF-7 cell proliferation	ic50	0.0001	uM
1,3-diethyl-2-(4-hydroxyphenyl)-3H-inden-5-ol	254648: Transcriptional activation of estrogen receptor alpha in U2OS cell using estrogen-regulated luciferase reporter gene plasmid upon incubation for 20-30 mins at RT	ec50	0.0001	uM
(NE)-N-[(3,4-diphenylphenyl)methylidene]hydroxylamine	69873: Relative binding affinity for human estrogen receptor alpha compared to [3H]estradiol	ki	0.0001	uM
(2S)-2-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-8-ol	1591918: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by FITC/Hoechst 33342 staining based immunofluorescence imaging analysis	ic50	0.0001	uM
3-[(1R,3R)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol	1768138: Antagonist activity at estrogen receptor in human T47D cells incubated for 18 hrs by ultra high sensitivity luminescence reporter gene assay	ic50	0.0001	uM
(1R,3R)-1-[2,6-difluoro-4-(1-propylazetidin-3-yl)oxyphenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole	1658825: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by FITC/Hoechst staining based immunofluorescence imaging analysis	ic50	0.0001	uM
(1R,3R)-1-[4-[2-[3-(difluoromethyl)azetidin-1-yl]ethoxy]-2,6-difluorophenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole	1658825: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by FITC/Hoechst staining based immunofluorescence imaging analysis	ic50	0.0001	uM
(1R,3R)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole	1512607: Induction of ERalpha degradation in human MCF7 cells assessed as downregulation of ER alpha receptor expression measured after 18 to 22 hrs by immunofluorescence assay	ic50	0.0001	uM
3-[(1R,3R)-1-[2,6-difluoro-4-[1-(3-fluoropropyl)azetidin-3-yl]oxyphenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol	1768138: Antagonist activity at estrogen receptor in human T47D cells incubated for 18 hrs by ultra high sensitivity luminescence reporter gene assay	ic50	0.0001	uM
(1R,3R)-1-[2,6-difluoro-4-(1-prop-2-ynylazetidin-3-yl)oxyphenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole	1658825: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by FITC/Hoechst staining based immunofluorescence imaging analysis	ic50	0.0001	uM
3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-7-fluoro-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol	1768138: Antagonist activity at estrogen receptor in human T47D cells incubated for 18 hrs by ultra high sensitivity luminescence reporter gene assay	ic50	0.0001	uM
(1R,3R)-1-[2,6-difluoro-4-[2-[(3R)-3-(fluoromethyl)pyrrolidin-1-yl]ethoxy]phenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole	1658825: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by FITC/Hoechst staining based immunofluorescence imaging analysis	ic50	0.0001	uM
3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-6-fluoro-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol	1768138: Antagonist activity at estrogen receptor in human T47D cells incubated for 18 hrs by ultra high sensitivity luminescence reporter gene assay	ic50	0.0001	uM
3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol	1768138: Antagonist activity at estrogen receptor in human T47D cells incubated for 18 hrs by ultra high sensitivity luminescence reporter gene assay	ic50	0.0001	uM
3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-5-fluoro-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol	1768138: Antagonist activity at estrogen receptor in human T47D cells incubated for 18 hrs by ultra high sensitivity luminescence reporter gene assay	ic50	0.0001	uM
(1R,3R)-1-[2,6-difluoro-4-(1-prop-2-enylazetidin-3-yl)oxyphenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole	1658825: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by FITC/Hoechst staining based immunofluorescence imaging analysis	ic50	0.0001	uM
(19R)-19-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8,18-dioxatetracyclo[9.8.0.02,7.012,17]nonadeca-1(11),2(7),3,5,12(17),13,15-heptaene-5,15-diol	1624901: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by Alexafluor-488 conjugate anti-mouse IgG antibody/Hoechst 33342 staining based immunofluorescence imaging analysis	ic50	0.0001	uM
(19S)-19-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8,18-dioxatetracyclo[9.8.0.02,7.012,17]nonadeca-1(11),2(7),3,5,12(17),13,15-heptaene-5,15-diol	1624901: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by Alexafluor-488 conjugate anti-mouse IgG antibody/Hoechst 33342 staining based immunofluorescence imaging analysis	ic50	0.0001	uM
19-[4-[2-[(3R)-3-(fluoromethyl)pyrrolidin-1-yl]ethoxy]phenyl]-8,18-dioxatetracyclo[9.8.0.02,7.012,17]nonadeca-1(11),2(7),3,5,12(17),13,15-heptaene-5,15-diol	1624901: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by Alexafluor-488 conjugate anti-mouse IgG antibody/Hoechst 33342 staining based immunofluorescence imaging analysis	ic50	0.0001	uM
19-[4-[(2S)-2-[(3R)-3-(fluoromethyl)pyrrolidin-1-yl]propoxy]phenyl]-8,18-dioxatetracyclo[9.8.0.02,7.012,17]nonadeca-1(11),2(7),3,5,12(17),13,15-heptaene-5,15-diol	1624901: Induction of ERalpha degradation in human MCF7 cells after 4 hrs by Alexafluor-488 conjugate anti-mouse IgG antibody/Hoechst 33342 staining based immunofluorescence imaging analysis	ic50	0.0001	uM
[4-[2-(dodecylamino)ethoxy]phenyl]-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone	1301304: Antagonist activity at ERalpha (unknown origin) transfected in 17beta-estradiol induced-HEK293 cells assessed as inhibition of estradiol-mediated protein transcriptional activity after 8 hrs by Luciferase reporter gene assay	ic50	0.0001	uM
(E)-3-[4-[[2-(4-chloro-2,6-dimethylbenzoyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl]prop-2-enoic acid	1431903: Induction of ERalpha degradation in tamoxifen-sensitive human MCF7:WS8 cells after 24 hrs by CellTag 700 staining based In-cell western assay	ec50	0.0001	uM
(6S,8R)-6-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-7-(2-fluoro-2-methylpropyl)-8-methyl-3,6,8,9-tetrahydropyrazolo[4,5-f]isoquinoline	1681503: Induction of ERalpha degradation in human MCF7 cells assessed as decrease in ER-alpha level incubated for 18 to 24 hrs by Alexa fluor 488/Hoechst staining based immunofluorescence imaging analysis	ic50	0.0001	uM
(6S,8R)-7-[(1-fluorocyclopropyl)methyl]-6-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]-2-methoxyphenyl]-8-methyl-3,6,8,9-tetrahydropyrazolo[4,5-f]isoquinoline	1681503: Induction of ERalpha degradation in human MCF7 cells assessed as decrease in ER-alpha level incubated for 18 to 24 hrs by Alexa fluor 488/Hoechst staining based immunofluorescence imaging analysis	ic50	0.0001	uM
3-[(1R,3R)-1-[2,6-difluoro-4-[2-(3-fluoropropylamino)ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol	2027451: Induction of ERalpha degradation in human MCF7 cells assessed as downregulation of ERaplha by multiplexed assay	ic50	0.0001	uM
2,2-difluoro-3-[(1R,3R)-1-[4-[2-(3-fluoropropylamino)ethoxy]-2-methoxyphenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]propan-1-ol	2027451: Induction of ERalpha degradation in human MCF7 cells assessed as downregulation of ERaplha by multiplexed assay	ic50	0.0001	uM
N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-3,6,8,9-tetrahydropyrazolo[4,5-f]isoquinolin-6-yl]pyridin-3-amine	1681460: Induction of ERalpha degradation in human MCF7 cells assessed as decrease in ERalpha expression in presence of cycloheximide by Western blot analysis	ic50	0.0001	uM
N-[4-[(6S,8R)-7-(2,2-difluoroethyl)-8-methyl-3,6,8,9-tetrahydropyrazolo[4,5-f]isoquinolin-6-yl]-3-methoxyphenyl]-1-(3-fluoropropyl)azetidin-3-amine	1681503: Induction of ERalpha degradation in human MCF7 cells assessed as decrease in ER-alpha level incubated for 18 to 24 hrs by Alexa fluor 488/Hoechst staining based immunofluorescence imaging analysis	ic50	0.0001	uM
1-(3-fluoropropyl)-N-[3-methoxy-4-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-3,6,8,9-tetrahydropyrazolo[4,5-f]isoquinolin-6-yl]phenyl]azetidin-3-amine	1681503: Induction of ERalpha degradation in human MCF7 cells assessed as decrease in ER-alpha level incubated for 18 to 24 hrs by Alexa fluor 488/Hoechst staining based immunofluorescence imaging analysis	ic50	0.0001	uM
2-fluoro-6-[(6S,8R)-1-fluoro-8-methyl-7-(2,2,2-trifluoroethyl)-2,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-N-[1-(3-fluoropropyl)azetidin-3-yl]pyridin-3-amine	1726310: Induction of ERalpha degradation in human MCF7 cells incubated for 18 to 22 hrs by immuno-fluorescence assay	ic50	0.0001	uM
5-fluoro-N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,3-trifluoropropyl)-3,6,8,9-tetrahydropyrazolo[4,5-f]isoquinolin-6-yl]pyridin-3-amine	1726310: Induction of ERalpha degradation in human MCF7 cells incubated for 18 to 22 hrs by immuno-fluorescence assay	ic50	0.0001	uM
5-fluoro-6-[(6S,8R)-1-fluoro-8-methyl-7-(2,2,2-trifluoroethyl)-2,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-N-[1-(3-fluoropropyl)azetidin-3-yl]pyridin-3-amine	1726310: Induction of ERalpha degradation in human MCF7 cells incubated for 18 to 22 hrs by immuno-fluorescence assay	ic50	0.0001	uM
1-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]azetidine-3-carboxamide	1810416: Induction of degradation of ERalpha in human MCF7 cells incubated for 4 hrs in presence of anti-ERalpha rabbit monoclonal antibodies measured after 4 hrs by immunofluorescent staining based assay	ec50	0.0001	uM
3-fluoro-N-[2-[4-fluoro-2-methyl-3-[(1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenoxy]ethyl]propan-1-amine	2027451: Induction of ERalpha degradation in human MCF7 cells assessed as downregulation of ERaplha by multiplexed assay	ic50	0.0001	uM
3-[(1R,3R)-1-[2,6-difluoro-3-[2-(3-fluoropropylamino)ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol	2027451: Induction of ERalpha degradation in human MCF7 cells assessed as downregulation of ERaplha by multiplexed assay	ic50	0.0001	uM
4-[N-(2-chlorophenyl)-C-(4-hydroxyphenyl)carbonimidoyl]benzene-1,3-diol	1127140: Agonist activity at ERalpha (unknown origin) expressed in human HepG2 cells assessed as transcriptional activation after 24 hrs by ERE-luciferase reporter gene assay	ec50	0.0001	uM
(E)-3-[4-[2-adamantylidene-(4-hydroxyphenyl)methyl]phenyl]-N,N-bis(2-hydroxyethyl)prop-2-enamide	1446048: Displacement of [3H]estradiol from full-length human ERalpha receptor by scintillation counting	ki	0.0001	uM
4-[(E)-4-(4-hydroxyphenyl)-10-[methyl-[3-(4,4,5,5,5-pentafluoropentylsulfanyl)propyl]amino]dec-3-en-3-yl]phenol	248483: Inhibition of ER-MDA-MB 231 breast cancer cell proliferation over 200 hr	ic50	0.0002	uM
6-(4-fluorophenyl)-5-[4-(2-piperidin-1-ylethoxy)phenoxy]naphthalen-2-ol	290754: Displacement of [3H]estradiol from human recombinant ERalpha	ki	0.0002	uM
(E)-3-[4-[[2-[2-(1,1-difluoroethyl)-4-fluorophenyl]-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl]prop-2-enoic acid	1469719: Induction of selective estrogen receptor alpha degradation in human MCF7 cells after 18 to 24 hrs by in-cell Western analysis	ic50	0.0002	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects abundance, decreases chemical synthesis, decreases cleavage, affects folding, decreases reaction (+21 more)	426
bisphenol A	decreases reaction, affects expression, affects localization, decreases degradation, decreases methylation (+17 more)	172
Fulvestrant	affects binding, affects folding, decreases activity, increases activity, decreases methylation (+14 more)	104
Tamoxifen	affects expression, affects methylation, decreases activity, increases response to substance, increases reaction (+14 more)	95
Genistein	decreases activity, increases expression, decreases expression, affects cotreatment, affects binding (+6 more)	67
afimoxifene	increases activity, increases reaction, affects localization, affects cotreatment, decreases reaction (+9 more)	50
Diethylstilbestrol	affects binding, affects cotreatment, increases expression, decreases reaction, increases reaction (+4 more)	50
Resveratrol	affects localization, affects binding, increases reaction, increases activity, decreases expression (+11 more)	34
Raloxifene Hydrochloride	increases expression, affects cotreatment, increases cleavage, affects activity, affects folding (+11 more)	33
daidzein	affects binding, increases activity, decreases expression, increases expression, affects reaction (+5 more)	23
Coumestrol	affects binding, increases activity, increases reaction, increases expression, affects response to substance (+4 more)	23
Methoxychlor	decreases reaction, increases reaction, affects response to substance, affects binding, affects cotreatment (+4 more)	23
Tetrachlorodibenzodioxin	increases expression, increases response to substance, affects reaction, decreases expression, increases reaction (+7 more)	23
bisphenol S	affects binding, increases activity, decreases reaction, increases expression, decreases methylation (+8 more)	22
Ethinyl Estradiol	affects binding, increases activity, decreases reaction, decreases expression, increases reaction (+1 more)	22
o,p’-DDT	decreases reaction, affects binding, decreases expression, affects cotreatment, affects expression (+3 more)	21
nonylphenol	decreases reaction, increases activity, increases reaction, affects activity, decreases expression (+4 more)	21
bisphenol AF	affects cotreatment, decreases reaction, decreases activity, increases secretion, increases expression (+5 more)	20
Estrone	affects binding, increases activity, decreases reaction, increases response to substance, increases reaction (+1 more)	18
Zearalenone	decreases activity, decreases expression, increases expression, decreases reaction, affects localization (+4 more)	17
4-nonylphenol	decreases reaction, decreases expression, affects binding, increases activity, affects cotreatment (+1 more)	16
DDT	decreases expression, affects cotreatment, increases expression, affects binding, increases activity	16
2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane	increases reaction, increases expression, affects binding, increases activity, decreases reaction	15
Diethylhexyl Phthalate	increases reaction, decreases reaction, affects cotreatment, increases expression, affects binding (+4 more)	15
4-tert-octylphenol	increases expression, affects binding, increases activity, decreases reaction, increases reaction	14
bisphenol B	affects activity, affects cotreatment, increases expression, affects localization, affects binding (+4 more)	14
Benzo(a)pyrene	affects binding, affects activity, affects methylation, increases activity, increases expression (+6 more)	14
Chlordecone	affects binding, increases activity, decreases reaction, increases expression	14
Dichlorodiphenyl Dichloroethylene	increases activity, affects binding, affects cotreatment, decreases expression, decreases reaction (+1 more)	13
Endosulfan	increases activity, increases reaction, decreases expression, decreases reaction, affects binding (+3 more)	13

ChEMBL screening assays

2435 unique, capped per target: 2037 binding, 363 functional, 35 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004750	Binding	Binding affinity to human ERalpha expressed in yeast relative to estradiol	Daucane phytoestrogens: a structure-activity study. — J Nat Prod
CHEMBL1010834	Functional	Antagonist activity at human ERalpha receptor expressed in HEC1 cells assessed as transcriptional activation after 24 hrs by luciferase reporter gene assay	Analogs of methyl-piperidinopyrazole (MPP): antiestrogens with estrogen receptor alpha selective activity. — Bioorg Med Chem Lett
CHEMBL1647191	ADMET	Antagonist activity at human ERalpha receptor expressed in human MCF7:D5L cells co-expressing ERE assessed as inhibition of estradiol-induced of luciferase gene expression at 1 uM after 18 hrs relative to ICI182780	New hydroxystilbenoid derivatives endowed with neuroprotective activity and devoid of interference with estrogen and aryl hydrocarbon receptor-mediated transcription. — Bioorg Med Chem

Cellosaurus cell lines

41 cell lines: 20 cancer cell line, 6 embryonic stem cell, 5 induced pluripotent stem cell, 5 transformed cell line, 2 telomerase immortalized cell line, 1 conditionally immortalized cell line, 1 finite cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_2485	HeLa9903	Cancer cell line	Female
CVCL_3380	HeLa 422	Cancer cell line	Female
CVCL_3381	HeLa 432	Cancer cell line	Female
CVCL_3398	MCF7-422	Cancer cell line	Female
CVCL_3399	MCF7-432	Cancer cell line	Female
CVCL_3400	MCF7-488X1	Cancer cell line	Female
CVCL_3401	MCF7-490X1	Cancer cell line	Female
CVCL_4Y53	MCF-7:2A	Cancer cell line	Female
CVCL_A1K4	SEES3-1V human ESR1, clone1	Embryonic stem cell	Male
CVCL_A1K5	SEES3-1V human ESR1, clone2	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT00040222	Not specified	COMPLETED	Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer
NCT02557776	Not specified	COMPLETED	Written Genetic Counseling and Mutation Analysis of BRCA1 and BRCA2 to Patients With Breast Cancer
NCT03495544	Not specified	UNKNOWN	Study Estimating Association Between Germline Mutations and PD-L1 Expression in Breast Cancer
NCT03959267	Not specified	COMPLETED	Testing a Culturally Adapted Telephone Genetic Counseling Intervention
NCT04058418	Not specified	COMPLETED	Specialist Recommendation on FBC (Familial Breast Cancer) Chemoprevention Prescribing
NCT04125914	Not specified	ACTIVE_NOT_RECRUITING	Weight Management and Health Behavior Intervention in Lowering Cancer Risk for BRCA Positive and Lynch Syndrome Families
NCT04169542	Not specified	RECRUITING	Impact of COVID-19 Pandemic on Out-of-Pocket Costs, Lost Wages, and Unemployment in Patients With Breast Cancer Undergoing Breast Surgery
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT07292246	Not specified	RECRUITING	A Prospective CohorT Study of HandX - Assisted ENdoscopic MAstectomy: Feasibility and Safety (ATHENA I Study)
NCT07307664	Not specified	RECRUITING	Increasing Germline Genetic Testing for Patients With Cancer