NR3C1

Summary

NR3C1 (nuclear receptor subfamily 3 group C member 1, HGNC:7978) is a protein-coding gene on chromosome 5q31.3, encoding Glucocorticoid receptor (P04150). Receptor for glucocorticoids (GC).

This gene encodes glucocorticoid receptor, which can function both as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription, and as a regulator of other transcription factors. This receptor is typically found in the cytoplasm, but upon ligand binding, is transported into the nucleus. It is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues. Mutations in this gene are associated with generalized glucocorticoid resistance. Alternative splicing of this gene results in transcript variants encoding either the same or different isoforms. Additional isoforms resulting from the use of alternate in-frame translation initiation sites have also been described, and shown to be functional, displaying diverse cytoplasm-to-nucleus trafficking patterns and distinct transcriptional activities (PMID:15866175).

Source: NCBI Gene 2908 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glucocorticoid resistance (Strong, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 314 total — 12 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 82
• Druggable target: yes — 162 molecules with ChEMBL bioactivity
• Transcription factor: yes — 308 downstream targets (CollecTRI)
• MANE Select transcript: NM_000176

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7978
Approved symbol	NR3C1
Name	nuclear receptor subfamily 3 group C member 1
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Aliases	GR
Ensembl gene	ENSG00000113580
Ensembl biotype	protein_coding
OMIM	138040
Entrez	2908

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 27 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000231509, ENST00000343796, ENST00000394464, ENST00000394466, ENST00000415690, ENST00000424646, ENST00000502500, ENST00000502892, ENST00000503201, ENST00000503701, ENST00000504336, ENST00000504572, ENST00000505058, ENST00000508760, ENST00000510170, ENST00000514699, ENST00000652686, ENST00000870492, ENST00000870493, ENST00000870494, ENST00000870495, ENST00000870496, ENST00000870497, ENST00000870498, ENST00000870499, ENST00000935689, ENST00000935690, ENST00000971221, ENST00000971222, ENST00000971223

RefSeq mRNA: 21 — MANE Select: NM_000176 NM_000176, NM_001018074, NM_001018075, NM_001018076, NM_001018077, NM_001020825, NM_001024094, NM_001204258, NM_001204259, NM_001204260, NM_001204261, NM_001204262, NM_001204263, NM_001204264, NM_001204265, NM_001364180, NM_001364181, NM_001364182, NM_001364183, NM_001364184, NM_001364185

CCDS: CCDS34258, CCDS4278, CCDS47298

Canonical transcript exons

ENST00000394464 — 9 exons

Exon	Start	End
ENSE00001082911	143282568	143282725
ENSE00001082912	143295460	143295590
ENSE00001082913	143298668	143298812
ENSE00001082914	143300485	143300763
ENSE00001171430	143399656	143400852
ENSE00001816085	143403211	143403686
ENSE00003577193	143310097	143310213
ENSE00003587825	143314002	143314168
ENSE00003846106	143277934	143282041

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 99.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.6605 / max 646.8822, expressed in 1771 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63944	11.2927	1646
63948	7.2211	1557
63942	2.4894	460
63946	0.9043	554
63949	0.8165	442
63945	0.5111	284
63943	0.4811	158
63951	0.3294	166
63952	0.3097	96
63955	0.1745	91

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.32	gold quality
tibia	UBERON:0000979	99.14	gold quality
cartilage tissue	UBERON:0002418	98.65	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.49	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.31	gold quality
superficial temporal artery	UBERON:0001614	98.30	gold quality
visceral pleura	UBERON:0002401	98.28	gold quality
synovial joint	UBERON:0002217	98.26	gold quality
nipple	UBERON:0002030	98.23	gold quality
parietal pleura	UBERON:0002400	98.20	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.19	gold quality
skin of hip	UBERON:0001554	98.12	gold quality
pleura	UBERON:0000977	98.11	gold quality
biceps brachii	UBERON:0001507	98.11	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.10	gold quality
calcaneal tendon	UBERON:0003701	98.10	gold quality
trabecular bone tissue	UBERON:0002483	97.99	gold quality
vastus lateralis	UBERON:0001379	97.81	gold quality
penis	UBERON:0000989	97.78	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.68	gold quality
amniotic fluid	UBERON:0000173	97.65	gold quality
trigeminal ganglion	UBERON:0001675	97.62	gold quality
deltoid	UBERON:0001476	97.51	gold quality
mammary duct	UBERON:0001765	97.44	gold quality
quadriceps femoris	UBERON:0001377	97.42	gold quality
upper leg skin	UBERON:0004262	97.42	gold quality
cervix squamous epithelium	UBERON:0006922	97.40	gold quality
germinal epithelium of ovary	UBERON:0001304	97.39	gold quality
epithelium of mammary gland	UBERON:0003244	97.35	gold quality
gluteal muscle	UBERON:0002000	97.31	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-120	yes	796.64
E-MTAB-8142	yes	83.43
E-CURD-122	yes	43.16
E-MTAB-8410	yes	18.24
E-CURD-95	no	1089.43
E-CURD-89	no	992.37
E-CURD-112	no	2.90
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

308 targets.

Target	Regulation
ABCA1	Repression
ABCB1	Activation
ABCC2	Unknown
ABCG2	Activation
ABCG4
ACAT1
ACO1	Unknown
ADAM2
ADIPOR2	Activation
ADM	Activation
ADRB1	Repression
AFP	Repression
AGT	Unknown
AHR	Activation
ALOX12	Unknown
ALOX15B	Repression
AMACR	Unknown
ANGPTL4
ANXA1	Unknown
AP1	Repression
AR	Unknown
ART3	Unknown
ASAH2	Activation
ATF2	Repression
ATP1B1	Repression
BAD	Activation
BAX	Activation
BCL2	Repression
BCL2L1	Unknown
BDNF	Unknown

JASPAR motifs

Motif	Name	Family
MA0113.1	NR3C1	Steroid hormone receptors (NR3)
MA0113.2	NR3C1	Steroid hormone receptors (NR3)
MA0113.3	NR3C1	Steroid hormone receptors (NR3)
MA0113.4	NR3C1	Steroid hormone receptors (NR3)

JASPAR matrix evidence (PMIDs): PMID:15563547

Upstream regulators (CollecTRI, top): AP1, AR, ARHGAP35, CEBPB, CLOCK, CREB1, CREM, DAXX, EGR1, ERG, ESR1, FOS, FOXA1, GSK3A, GSK3B, HES1, HIF1A, JUN, KLF15, MYB, NCOA1, NCOR1, NFE2L2, NFIC, NFKB, NR0B1, NR1H3, NR1I3, NR2F2, NR3C1, NR4A1, NRF1, PELP1, PPARG, PTMS, RELA, SFPQ, SLC24A3, SP1, SPI1

miRNA regulators (miRDB)

312 targeting NR3C1, 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-98-3P	100.00	74.08	3907
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520

Literature-anchored findings (GeneRIF, showing 40)

• The findings show an association between rheumatoid arthritis and a polymorphism in the hGR gene that increased the stability of hGRbeta mRNA. (PMID:11708406)
• The counteracting action of cortisone against cortisol-induced apoptosis may take place partially through intervention of GC-receptors (GC-Rs), but may also be due to unknown pathway(s) different from those mediated by cellular GC-Rs. (PMID:11710540)
• Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene. (PMID:11932321)
• Results are consistent with a dynamic model in which GR first binds to chromatin after ligand activation, recruits a remodeling activity, facilitates transcription factor binding, and is simultaneously lost from the template. (PMID:11971959)
• Glucocorticoid receptor binding in twin pairs is affected by shared environment but not by shared genes (PMID:11983486)
• AUUUA motifs in the 3’UTR of human glucocorticoid receptor alpha and beta mRNA destabilize mRNA and decrease receptor protein expression (PMID:11996936)
• This study shows that both promoters 1B and 1C are important for the ubiquitous expression of the human glucocorticoid receptor gene. (PMID:12039077)
• Functional interaction between the pro-apoptotic DAP3 and the glucocorticoid receptor (PMID:12099703)
• There was a significantly higher expression of the GR is untreated RA patients than controls. Glucocorticoid treatment was associated with a strongly decreased GR density. (PMID:12114309)
• The glucocorticoid receptor: coding a diversity of proteins and responses through a single gene. Review. (PMID:12145329)
• Review. The roles of glucocorticoid receptor isoforms alpha and beta in the response to glucocorticoids in asthma are analyzed. (PMID:12237016)
• These findings suggest that JNK-mediated phosphorylation of the GR-Ser226 enhances GR nuclear export and may contribute to termination of GR-mediated transcription. (PMID:12351702)
• We identified a novel heterozygous mutation (C643R) in the ligand-binding domain in P30/OHK cells (PMID:12430185)
• The results of homology modelling of the human glucorticoid receptor (hGR) ligand-binding domain (LBD) based on the ligand-bound domain of the human estrogen receptor alpha (hERalpha) are reported. (PMID:12477485)
• data support the existence of a new pathway involving hSur2 for modulating GR transactivation processes (PMID:12581885)
• Ligand binding induces a conformational change dependent on ligand affinity. This decreases receptor mobility, probably by targeting it to relatively immobile nuclear domains with which it transiently associates. This also blocks immobilization by MG132. (PMID:12612067)
• Association of coronary artery disease with glucocorticoid receptor N363S variant. (PMID:12623935)
• Glucocorticoid receptor activates Bcl-XL during tumorigenesis (PMID:12637494)
• there are non-hormone-binding receptor forms of glucocorticoid receptor in addition to the native heterocomplex (PMID:12711001)
• Serine-arginine-rich protein p30 directs alternative splicing of glucocorticoid receptor pre-mRNA to glucocorticoid receptor beta in neutrophils. (PMID:12738786)
• Data show that differential recruitment of coactivators by progesterone and glucocorticoid receptors determines the assembly of coactivator complexes on target promoters to mediate specific transcription signals. (PMID:12748280)
• REVIEW: pathological and in vitro mutations and polymorphisms (PMID:12754700)
• investigation of dominant negative function of human glucocorticoid receptor beta (PMID:12773573)
• glucocorticoid receptor has a role in regulation of hypoxia-dependent gene expression (PMID:12810720)
• the ligand-binding domain of GR, but not the DNA-binding domain or the N-terminal activation domain, is required for GR-mediated transrepression of TGF-beta transactivation (PMID:12902338)
• Data show that the G allele may be a predisposing gene marker, glucocorticoid receptor gene intron 4 polymorphism contributes to the development of cerebral infarction in females. (PMID:12903052)
• Identification of the novel GRV575M variant in human bronchial epithelial cells using a molecular genetic selection scheme (PMID:12920235)
• GRalpha transcripts containing exons 1A3, 1B, and 1C contribute most to the intracellular level of GR mRNA and may be the most relevant for steroid-mediated apoptosis in T-lymphoblasts (PMID:12974633)
• identified genes transcriptionally activated by GR, in a translation-independent manner, in two human cell lines (PMID:14617768)
• Twelve polymorphisms in the NR3C1 gene were detected, two types of newly found haplotypes were associated with steroid-resistant idiopathic nephrotic syndrome, which might be responsible for steroid-resistance in partial idiopathic nephrotic syndrome. (PMID:14733805)
• promoter has several different steroid-responsive sequences (PMID:15044598)
• the role of Hsp90 in nuclear retention of GR after ligand withdrawal (PMID:15062560)
• Data report the crystal structures of two overlapped fragments of FK506-binding protein 52 and the heterocomplex of glucocorticoid receptors with heat-shock proteins 90. (PMID:15159550)
• Results reveal differential modulatory roles of the protein inhibitor of activated STAT proteins on the transcriptional properties of mineralocorticoid and glucocorticoid receptors. (PMID:15171715)
• a mutation of the glucocorticoid receptor gene may have a role in development of systemic lupus erythematosus (PMID:15212141)
• relaxin acts as GR agonist–a pathway pivotal to its effects on cytokine secretion by human macrophages (PMID:15289446)
• The ER22/23EK polymorphism is associated with a sex-specific, beneficial body composition at young-adult age, as well as greater muscle strength in males (PMID:15292341)
• hGRbeta suppresses the transcriptional activity of hGRalpha by competing with hGRalpha for binding to GRIP1, and possibly other p160 coactivators, through its preserved AF-1 (PMID:15459252)
• role of GR in glucocorticoid-regulated gene expression (PMID:15501915)
• the interaction between PPARgamma and GR may be responsible for the additive and synergistic inhibition of chemokine expression by PPARgamma agonists, glucocorticoids, and beta(2)-agonists (PMID:15531761)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nr3c1	ENSDARG00000025032
mus_musculus	Nr3c1	ENSMUSG00000024431
rattus_norvegicus	Nr3c1	ENSRNOG00000014096
drosophila_melanogaster	ERR	FBGN0035849

Paralogs (8): PGR (ENSG00000082175), ESR1 (ENSG00000091831), ESRRB (ENSG00000119715), ESR2 (ENSG00000140009), NR3C2 (ENSG00000151623), AR (ENSG00000169083), ESRRA (ENSG00000173153), ESRRG (ENSG00000196482)

Protein

Protein identifiers

Glucocorticoid receptor — P04150 (reviewed: P04150)

Alternative names: Nuclear receptor subfamily 3 group C member 1

All UniProt accessions (7): P04150, A0A494C0P1, D6RDA9, E5KQF5, E5KQF6, F1D8N4, Q3MSN4

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Involved in chromatin remodeling. Plays a role in rapid mRNA degradation by binding to the 5’ UTR of target mRNAs and interacting with PNRC2 in a ligand-dependent manner which recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Has transcriptional activation and repression activity. Mediates glucocorticoid-induced apoptosis. Promotes accurate chromosome segregation during mitosis. May act as a tumor suppressor. May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic gene expression. Acts as a dominant negative inhibitor of isoform Alpha. Has intrinsic transcriptional activity independent of isoform Alpha when both isoforms are coexpressed. Loses this transcription modulator function on its own. Has no hormone-binding activity. May play a role in controlling glucose metabolism by maintaining insulin sensitivity. Reduces hepatic gluconeogenesis through down-regulation of PEPCK in an isoform Alpha-dependent manner. Directly regulates STAT1 expression in isoform Alpha-independent manner. Has lower transcriptional activation activity than isoform Alpha. Exerts a dominant negative effect on isoform Alpha trans-repression mechanism. Increases activity of isoform Alpha. More effective than isoform Alpha in transcriptional activation, but not repression activity. Has transcriptional activation activity. Has transcriptional activation activity. Has transcriptional activation activity. Has highest transcriptional activation activity of all isoforms created by alternative initiation. Has transcriptional repression activity. Mediates glucocorticoid-induced apoptosis. Has transcriptional activation activity. Has transcriptional activation activity. Has lowest transcriptional activation activity of all isoforms created by alternative initiation. Has transcriptional repression activity.

Subunit / interactions. Heteromultimeric cytoplasmic complex with HSP90AA1, HSPA1A/HSPA1B, and FKBP5 or another immunophilin such as PPID, STIP1, or the immunophilin homolog PPP5C. Upon ligand binding FKBP5 dissociates from the complex and FKBP4 takes its place, thereby linking the complex to dynein and mediating transport to the nucleus, where the complex dissociates. Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23. Directly interacts with UNC45A. Binds to DNA as a homodimer, and as heterodimer with NR3C2 or the retinoid X receptor. Binds STAT5A and STAT5B homodimers and heterodimers. Interacts with NRIP1, POU2F1, POU2F2 and TRIM28. Interacts with several coactivator complexes, including the SMARCA4 complex, CREBBP/EP300, TADA2L (Ada complex) and p160 coactivators such as NCOA2 and NCOA6. Interaction with BAG1 inhibits transactivation. Interacts with HEXIM1 and TGFB1I1. Interacts with NCOA1. Interacts with NCOA3, SMARCA4, SMARCC1, SMARCD1, and SMARCE1. Interacts with CLOCK, CRY1 and CRY2 in a ligand-dependent fashion. Interacts with CIART. Interacts with RWDD3. Interacts with UBE2I/UBC9 and this interaction is enhanced in the presence of RWDD3. Interacts with GRIP1. Interacts with NR4A3 (via nuclear receptor DNA-binding domain), represses transcription activity of NR4A3 on the POMC promoter Nur response element (NurRE). Directly interacts with PNRC2 to attract and form a complex with UPF1 and DCP1A; the interaction leads to rapid mRNA degradation. Interacts with GSK3B. Interacts with FNIP1 and FNIP2. Interacts (via C-terminus) with HNRNPU (via C-terminus). Interacts with MCM3AP. Interacts (via domain NR LBD) with HSP90AA1 and HSP90AB1. In the absence of hormonal ligand, interacts with TACC1. Interacts (via NR LBD domain) with ZNF764 (via KRAB domain); the interaction regulates transcription factor activity of NR3C1 by directing its actions toward certain biologic pathways.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion. Cytoskeleton. Spindle. Microtubule organizing center. Centrosome. Chromosome. Nucleoplasm Nucleus. Cytoplasm Nucleus.

Tissue specificity. Widely expressed including bone, stomach, lung, liver, colon, breast, ovary, pancreas and kidney. In the heart, detected in left and right atria, left and right ventricles, aorta, apex, intraventricular septum, and atrioventricular node as well as whole adult and fetal heart. Widely expressed including brain, bone marrow, thymus, spleen, liver, kidney, pancreas, lung, fat, skeletal muscle, heart, placenta and blood leukocytes. Widely expressed.

Post-translational modifications. Acetylation by CLOCK reduces its binding to glucocorticoid response elements and its transcriptional activity. Increased proteasome-mediated degradation in response to glucocorticoids. Isoform Alpha-B appears to be more susceptible to proteolytic degradation than isoform Alpha. Phosphorylated in the absence of hormone; becomes hyperphosphorylated in the presence of glucocorticoid. The Ser-203, Ser-226 and Ser-404-phosphorylated forms are mainly cytoplasmic, and the Ser-211-phosphorylated form is nuclear. Phosphorylation at Ser-211 increases transcriptional activity. Phosphorylation at Ser-203, Ser-226 and Ser-404 decreases signaling capacity. Phosphorylation at Ser-404 may protect from glucocorticoid-induced apoptosis. Phosphorylation at Ser-203 and Ser-211 is not required in regulation of chromosome segregation. May be dephosphorylated by PPP5C, attenuates NR3C1 action. Ubiquitinated by UBR5, leading to its degradation: UBR5 specifically recognizes and binds ligand-bound NR3C1 when it is not associated with coactivators (NCOAs). In presence of NCOAs, the UBR5-degron is not accessible, preventing its ubiquitination and degradation. Sumoylation at Lys-277 and Lys-293 negatively regulates its transcriptional activity. Sumoylation at Lys-703 positively regulates its transcriptional activity in the presence of RWDD3. Sumoylation at Lys-277 and Lys-293 is dispensable whereas sumoylation at Lys-703 is critical for the stimulatory effect of RWDD3 on its transcriptional activity. Heat shock increases sumoylation in a RWDD3-dependent manner.

Disease relevance. Glucocorticoid resistance, generalized (GCCR) [MIM:615962] An autosomal dominant disease characterized by increased plasma cortisol concentration and high urinary free cortisol, resistance to adrenal suppression by dexamethasone, and the absence of Cushing syndrome typical signs. Clinical features include hypoglycemia, hypertension, metabolic alkalosis, chronic fatigue and profound anxiety. 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 ligand-binding domain is required for correct chromosome segregation during mitosis although ligand binding is not required.

Induction. Induced by TNF (at protein level). Induced by TNF and becomes the predominant isoform which may lead to glucocorticoid resistance (at protein level).

Polymorphism. Carriers of the 22-Glu-Lys-23 allele are relatively more resistant to the effects of GCs with respect to the sensitivity of the adrenal feedback mechanism than non-carriers, resulting in a better metabolic health profile. Carriers have a better survival than non-carriers, as well as lower serum CRP levels. The 22-Glu-Lys-23 polymorphism is associated with a sex-specific, beneficial body composition at young-adult age, as well as greater muscle strength in males.

Miscellaneous. High constitutive expression by neutrophils may provide a mechanism by which these cells escape glucocorticoid-induced cell death and up-regulation by pro-inflammatory cytokines such as IL8 further enhances their survival in the presence of glucocorticoids during inflammation. Can up- or down-modulate aggregation and nuclear localization of expanded polyglutamine polypeptides derived from AR and HD through specific regulation of gene expression. Aggregation and nuclear localization of expanded polyglutamine proteins are regulated cellular processes that can be modulated by this receptor, a well-characterized transcriptional regulator. Predominant physiological form. Due to a partial intron retention. Due to a partial intron retention. Lacks exons 5, 6 and 7. Found in glucocorticoid-resistant myeloma patients. Lacks exons 5, 6 and 7. Encoded by exons 2-7 plus several basepairs from the subsequent intron region. Lacks the ligand binding domain. Accounts for up to 10-20% of mRNAs. Produced by alternative initiation at Met-27 of isoform Alpha. Produced by alternative initiation at Met-27 of isoform Beta. Produced by alternative initiation at Met-86 of isoform Alpha. Produced by alternative initiation at Met-90 of isoform Alpha. Produced by alternative initiation at Met-98 of isoform Alpha. Produced by alternative initiation at Met-316 of isoform Alpha. Produced by alternative initiation at Met-331 of isoform Alpha. Produced by alternative initiation at Met-336 of isoform Alpha.

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

Isoforms (16)

UniProt ID	Names	Canonical?
P04150-1	Alpha, Alpha-A, GR-alphaA	yes
P04150-2	Beta, Beta-A
P04150-3	Alpha-2, Gamma
P04150-6	Beta-2
P04150-5	GR-A alpha
P04150-7	GR-A beta
P04150-4	GR-P
P04150-8	Alpha-B, GR-alphaB
P04150-9	Beta-B
P04150-10	10, hGRDelta313-338
P04150-11	Alpha-C1, GR-alphaC1
P04150-12	Alpha-C2, GR-alphaC2
P04150-13	Alpha-C3, GR-alphaC3
P04150-14	Alpha-D1, GR-alphaD1
P04150-15	Alpha-D2, GR-alphaD2
P04150-16	Alpha-D3, GR-alphaD3

RefSeq proteins (21): NP_000167, NP_001018084, NP_001018085, NP_001018086, NP_001018087, NP_001018661, NP_001019265, NP_001191187, NP_001191188, NP_001191189, NP_001191190, NP_001191191, NP_001191192, NP_001191193, NP_001191194, NP_001351109, NP_001351110, NP_001351111, NP_001351112, NP_001351113, NP_001351114 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001409	Glcrtcd_rcpt	Family
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR050200	Nuclear_hormone_rcpt_NR3	Family

Pfam: PF00104, PF00105, PF02155

UniProt features (149 total): mutagenesis site 37, sequence variant 28, modified residue 17, helix 15, strand 11, splice variant 11, region of interest 8, cross-link 7, compositionally biased region 6, sequence conflict 2, turn 2, zinc finger region 2, chain 1, domain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

58 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4UDD	X-RAY DIFFRACTION	1.8
5E69	X-RAY DIFFRACTION	1.85
4HN5	X-RAY DIFFRACTION	1.9
4P6W	X-RAY DIFFRACTION	1.95
8A9G	X-RAY DIFFRACTION	1.96
5CBY	X-RAY DIFFRACTION	2
5CBX	X-RAY DIFFRACTION	2
6X6E	X-RAY DIFFRACTION	2
5UC3	X-RAY DIFFRACTION	2.01
6YMO	X-RAY DIFFRACTION	2.02
6YO8	X-RAY DIFFRACTION	2.09
3K22	X-RAY DIFFRACTION	2.1
5NFP	X-RAY DIFFRACTION	2.1
8VKZ	X-RAY DIFFRACTION	2.13
3E7C	X-RAY DIFFRACTION	2.15
5VA7	X-RAY DIFFRACTION	2.15
6EL7	X-RAY DIFFRACTION	2.18
6EL9	X-RAY DIFFRACTION	2.19
5E6A	X-RAY DIFFRACTION	2.2
5CBZ	X-RAY DIFFRACTION	2.2
5E6C	X-RAY DIFFRACTION	2.2
5G5W	X-RAY DIFFRACTION	2.2
7PRX	X-RAY DIFFRACTION	2.2
5E6B	X-RAY DIFFRACTION	2.25
5VA0	X-RAY DIFFRACTION	2.29
1NHZ	X-RAY DIFFRACTION	2.3
4CSJ	X-RAY DIFFRACTION	2.3
5EMC	X-RAY DIFFRACTION	2.3
5EMP	X-RAY DIFFRACTION	2.3
5EMQ	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04150-F1	60.75	0.37

Functional residue map

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

Post-translational modifications (24): 1, 1, 8, 23, 45, 113, 134, 141, 203, 211, 226, 267, 404, 480, 492, 494, 495, 258, 277, 277 …

Mutagenesis-validated functional residues (37):

Position	Phenotype
277	strongly reduces sumoylation. almost complete loss of sumoylation; when associated with r-293.
293	strongly reduces sumoylation. almost complete loss of sumoylation; when associated with r-277.
316	abolishes expression of d-type isoforms; when associated with i-331 and i-336.
331	abolishes expression of d-type isoforms; when associated with i-316 and i-336.
336	abolishes expression of d-type isoforms; when associated with i-316 and i-331.
404	abolishes phosphorylation. does not affect translocation to the nucleus following ligand stimulation. increases protein
404	does not affect translocation to the nucleus following ligand stimulation.
480	decrease in acetylation and in repression of its transcriptional activity by clock-bmal1 heterodimer. complete loss in a
492	decrease in acetylation and in repression of its transcriptional activity by clock-bmal1 heterodimer. complete loss in a
494	decrease in acetylation and in repression of its transcriptional activity by clock-bmal1 heterodimer; when associated wi
495	decrease in acetylation and in repression of its transcriptional activity by clock-bmal1 heterodimer; when associated wi
585	reduces activation mediated by ligand binding domain; when associated with a-590.
590	reduces activation mediated by ligand binding domain; when associated with a-585.
602	increases solubility. no effect on transactivation by dexamethasone.
625	decreases transactivation by dexamethasone by 95%.
628	decreases dimerization and transactivation by dexamethasone; when associated with s-602.
703	slightly reduces sumoylation. inhibits the stimulatory effect of rwdd3 on its transcriptional activity.
1	abolishes expression of a-type isoforms.
27	abolishes expression of b-type isoforms.
86	abolishes expression of c-type isoforms; when associated with i-90 and i-98.
90	abolishes expression of c-type isoforms; when associated with i-86 and i-98.
98	abolishes expression of c-type isoforms; when associated with i-86 and i-90.
101	reduces transcription activation activity of isoform alpha-c3 by half.
101	reduces transcription activation activity of isoform alpha-c3 by half. suppresses apoptosis-inducing activity of isoform
106–107	reduces activity of isoform alpha-c3 by half.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-3371497	HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand
R-HSA-4090294	SUMOylation of intracellular receptors
R-HSA-8849473	PTK6 Expression
R-HSA-8939902	Regulation of RUNX2 expression and activity
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9768777	Regulation of NPAS4 gene transcription
R-HSA-383280	Nuclear Receptor transcription pathway

MSigDB gene sets: 858 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, AHRARNT_01, BIOCARTA_GCR_PATHWAY, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GCACCTT_MIR18A_MIR18B, RNGTGGGC_UNKNOWN, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_GLAND_MORPHOGENESIS, GOBP_BEHAVIOR, YAGI_AML_WITH_INV_16_TRANSLOCATION, PID_HNF3B_PATHWAY, GOBP_INFLAMMATORY_RESPONSE

GO Biological Process (36): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of gluconeogenesis (GO:0006111), chromatin organization (GO:0006325), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), apoptotic process (GO:0006915), chromosome segregation (GO:0007059), signal transduction (GO:0007165), glucocorticoid metabolic process (GO:0008211), response to wounding (GO:0009611), gene expression (GO:0010467), microglia differentiation (GO:0014004), adrenal gland development (GO:0030325), nuclear receptor-mediated steroid hormone signaling pathway (GO:0030518), regulation of glucocorticoid biosynthetic process (GO:0031946), synaptic transmission, glutamatergic (GO:0035249), maternal behavior (GO:0042711), positive regulation of neuron apoptotic process (GO:0043525), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), astrocyte differentiation (GO:0048708), cell division (GO:0051301), response to cortisol (GO:0051414), mammary gland duct morphogenesis (GO:0060603), motor behavior (GO:0061744), cellular response to steroid hormone stimulus (GO:0071383), cellular response to glucocorticoid stimulus (GO:0071385), cellular response to dexamethasone stimulus (GO:0071549), cellular response to transforming growth factor beta stimulus (GO:0071560), neuroinflammatory response (GO:0150076), positive regulation of miRNA transcription (GO:1902895), nuclear receptor-mediated corticosteroid signaling pathway (GO:0031958), nuclear receptor-mediated glucocorticoid signaling pathway (GO:0042921), positive regulation of DNA-templated transcription (GO:0045893), response to glucocorticoid (GO:0051384), response to ketone (GO:1901654)

GO Molecular Function (25): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), core promoter sequence-specific DNA binding (GO:0001046), 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), RNA binding (GO:0003723), nuclear receptor activity (GO:0004879), nuclear glucocorticoid receptor activity (GO:0004883), steroid binding (GO:0005496), zinc ion binding (GO:0008270), TBP-class protein binding (GO:0017025), protein kinase binding (GO:0019901), estrogen response element binding (GO:0034056), identical protein binding (GO:0042802), Hsp90 protein binding (GO:0051879), steroid hormone binding (GO:1990239), sequence-specific double-stranded DNA binding (GO:1990837), promoter-specific chromatin binding (GO:1990841), DNA binding (GO:0003677), protein binding (GO:0005515), lipid binding (GO:0008289), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (15): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrial matrix (GO:0005759), centrosome (GO:0005813), spindle (GO:0005819), cytosol (GO:0005829), membrane (GO:0016020), nuclear speck (GO:0016607), protein-containing complex (GO:0032991), synapse (GO:0045202), chromosome (GO:0005694), mitochondrion (GO:0005739), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Cellular responses to stress	1
SUMO E3 ligases SUMOylate target proteins	1
Signaling by PTK6	1
Transcriptional regulation by RUNX2	1
FOXO-mediated transcription	1
SARS-CoV Infections	1
Regulation of NPAS4 gene expression	1
Generic Transcription Pathway	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
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
transcription cis-regulatory region binding	3
DNA-binding transcription factor activity, RNA polymerase II-specific	3
intracellular membraneless organelle	3
DNA-templated transcription	2
intracellular membrane-bounded organelle	2
cytoplasm	2
negative regulation of DNA-templated transcription	1
gluconeogenesis	1
regulation of glucose metabolic process	1
regulation of carbohydrate biosynthetic process	1
cellular component organization	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell cycle process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
steroid metabolic process	1
response to stress	1
macromolecule biosynthetic process	1
central nervous system development	1
glial cell differentiation	1
macrophage differentiation	1
endocrine system development	1
gland development	1
steroid hormone receptor signaling pathway	1
nuclear receptor-mediated signaling pathway	1
glucocorticoid biosynthetic process	1
regulation of glucocorticoid metabolic process	1
regulation of steroid hormone biosynthetic process	1

Protein interactions and networks

STRING

5547 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NR3C1	FKBP5	Q13451	998
NR3C1	HSP90AA1	P07900	996
NR3C1	HSP90AB1	P08238	994
NR3C1	HSPA4	P34932	979
NR3C1	FOS	P01100	958
NR3C1	FKBP4	Q02790	954
NR3C1	STAT3	P40763	932
NR3C1	JUN	P05412	922
NR3C1	CRY1	Q16526	901
NR3C1	NCOA2	Q15596	893
NR3C1	TP53	P04637	875
NR3C1	CRH	P06850	873
NR3C1	NTRK2	Q16620	868
NR3C1	PPARGC1A	Q9UBK2	861
NR3C1	POMC	P01189	855

IntAct

165 interactions, top by confidence:

A	B	Type	Score
NR3C1	HSP90AA1	psi-mi:“MI:0915”(physical association)	0.770
NR3C1	HSP90AA1	psi-mi:“MI:0914”(association)	0.770
	NR3C1	psi-mi:“MI:0407”(direct interaction)	0.670
	NR3C1	psi-mi:“MI:0915”(physical association)	0.670
ABCD4	ABCD4	psi-mi:“MI:0914”(association)	0.640
NR3C1	HSPA1A	psi-mi:“MI:0914”(association)	0.640
NR3C1	HSPA1A	psi-mi:“MI:0915”(physical association)	0.640
EGFR	NR3C1	psi-mi:“MI:0915”(physical association)	0.630
NR3C1	EGFR	psi-mi:“MI:0915”(physical association)	0.630
AKT1	NR3C1	psi-mi:“MI:0915”(physical association)	0.610
NR3C1	AKT1	psi-mi:“MI:0915”(physical association)	0.610
NR3C1	AKT1	psi-mi:“MI:0407”(direct interaction)	0.610
AKT1	NR3C1	psi-mi:“MI:0217”(phosphorylation reaction)	0.610
SOX14	NR3C1	psi-mi:“MI:0915”(physical association)	0.560
SEPTIN6	NR3C1	psi-mi:“MI:0915”(physical association)	0.560
NR3C1	Mvp	psi-mi:“MI:0407”(direct interaction)	0.530
NR3C1	Mvp	psi-mi:“MI:0915”(physical association)	0.530
SMC1A	PDS5B	psi-mi:“MI:0914”(association)	0.530

BioGRID (1799): NR3C1 (Reconstituted Complex), NR3C1 (Affinity Capture-Western), NR3C1 (Reconstituted Complex), NR3C1 (Affinity Capture-Western), NR3C1 (Affinity Capture-Western), TTC5 (Affinity Capture-Western), NR3C1 (Affinity Capture-Western), vpr (Reconstituted Complex), vpr (Affinity Capture-Western), NR3C1 (Affinity Capture-Western), NR3C1 (Biochemical Activity), NR3C1 (Two-hybrid), NR3C1 (Biochemical Activity), NR3C1 (Affinity Capture-Western), NR3C1 (Reconstituted Complex)

ESM2 similar proteins: A0A1L8GSA2, A0A1L8H0H2, A0JN51, A0JP82, A2AWL7, A2BGM5, A2RRX6, F8VPJ6, K9JHZ4, O13186, O46567, O54826, O89091, P04150, P08235, P15822, P22199, P32519, P36197, P37275, P48552, P55197, P59759, P79269, P79686, Q29131, Q2KHR2, Q3YC04, Q4JM28, Q5R9P5, Q60775, Q61321, Q62947, Q64318, Q68DE3, Q6XLJ0, Q8AYC1, Q8AYC2, Q8BMA5, Q8IZQ8

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

119 interactions.

A	Effect	B	Mechanism
NR2F2	“up-regulates quantity by expression”	NR3C1	“transcriptional regulation”
NR3C1	“up-regulates quantity by expression”	NR2F2	“transcriptional regulation”
NR3C1	“down-regulates quantity by repression”	NR4A1	“transcriptional regulation”
NR3C1	“down-regulates quantity by repression”	NR4A2	“transcriptional regulation”
NR3C1	“down-regulates quantity by repression”	NR4A3	“transcriptional regulation”
NR4A1	“down-regulates quantity by repression”	NR3C1	“transcriptional regulation”
MAPK14	up-regulates	NR3C1	phosphorylation
CDK5	“down-regulates activity”	NR3C1	phosphorylation
dexamethasone	up-regulates	NR3C1	“chemical activation”
GSK3B	“down-regulates activity”	NR3C1	phosphorylation
AKT	down-regulates	NR3C1	phosphorylation
PPP5C	“down-regulates activity”	NR3C1	dephosphorylation
FKBP5	down-regulates	NR3C1	binding
HSP90AA1	down-regulates	NR3C1	binding
HSPA1A	down-regulates	NR3C1	binding
SGK1	“up-regulates activity”	NR3C1	phosphorylation
HES1	“down-regulates quantity by repression”	NR3C1	“transcriptional regulation”
NR3C1	“down-regulates quantity by repression”	JUN	“transcriptional regulation”
NR3C1	“down-regulates quantity by repression”	NFKB1	“transcriptional regulation”
PELP1	“up-regulates quantity by expression”	NR3C1	“transcriptional regulation”
NR3C1	“up-regulates quantity by expression”	NCOA1	“transcriptional regulation”
NR3C1	up-regulates	CAV1	binding
NR3C1	“up-regulates quantity by expression”	HNF4A	“transcriptional regulation”
NR3C1	up-regulates	LCK	binding
betamethasone	up-regulates	NR3C1	“chemical activation”
budesonide	up-regulates	NR3C1	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 140 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
VEGFR2 mediated vascular permeability	5	19.6×	6e-04
ESR-mediated signaling	11	13.6×	3e-07
Signaling by Nuclear Receptors	10	9.8×	1e-05
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	5	9.3×	7e-03
Adipogenesis	6	9.0×	3e-03
Transcriptional regulation of white adipocyte differentiation	7	8.7×	1e-03
Cellular response to chemical stress	6	8.2×	4e-03
Extra-nuclear estrogen signaling	5	8.2×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
mRNA transcription by RNA polymerase II	5	12.9×	8e-03
positive regulation of miRNA transcription	5	11.3×	1e-02
negative regulation of protein ubiquitination	5	11.2×	1e-02
protein import into nucleus	7	7.9×	7e-03
cytokine-mediated signaling pathway	7	7.1×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	5
Uncertain significance	218
Likely benign	39
Benign	11

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1451274	NM_000176.3(NR3C1):c.1435C>T (p.Arg479Ter)	Pathogenic
16147	NM_000176.3(NR3C1):c.1922A>T (p.Asp641Val)	Pathogenic
16148	NM_000176.3(NR3C1):c.1891_1892+2del	Pathogenic
16149	NM_000176.3(NR3C1):c.2259A>T (p.Leu753Phe)	Pathogenic
16151	NM_000176.3(NR3C1):c.1676T>A (p.Ile559Asn)	Pathogenic
16152	NM_000176.3(NR3C1):c.2241T>G (p.Ile747Met)	Pathogenic
16153	NM_000176.3(NR3C1):c.1712T>C (p.Val571Ala)	Pathogenic
16155	NM_000176.3(NR3C1):c.2318T>C (p.Leu773Pro)	Pathogenic
16158	NM_000176.3(NR3C1):c.2209T>C (p.Phe737Leu)	Pathogenic
3246454	NC_000005.9:g.(?142779201)(142780404_?)del	Pathogenic
3591808	NM_000176.3(NR3C1):c.1835del (p.Ser612fs)	Pathogenic
3591819	NM_000176.3(NR3C1):c.1405C>T (p.Arg469Ter)	Pathogenic
2432327	NM_000176.3(NR3C1):c.1185-2A>G	Likely pathogenic
3591801	NM_000176.3(NR3C1):c.2186T>C (p.Val729Ala)	Likely pathogenic
3591834	NM_000176.3(NR3C1):c.678_679delinsA (p.Pro227fs)	Likely pathogenic
3893191	NM_000176.3(NR3C1):c.2009T>C (p.Leu670Pro)	Likely pathogenic
4278220	NM_000176.3(NR3C1):c.2182-1G>A	Likely pathogenic

SpliceAI

1805 predictions. Top by Δscore:

Variant	Effect	Δscore
5:143281922:T:TA	donor_gain	1.0000
5:143282565:TACT:T	donor_loss	1.0000
5:143282566:A:AC	donor_gain	1.0000
5:143282566:ACTT:A	donor_gain	1.0000
5:143282567:C:CT	donor_gain	1.0000
5:143282567:CT:C	donor_gain	1.0000
5:143282567:CTT:C	donor_gain	1.0000
5:143282567:CTTC:C	donor_gain	1.0000
5:143282567:CTTCA:C	donor_gain	1.0000
5:143282569:T:TA	donor_gain	1.0000
5:143282722:GGAA:G	acceptor_gain	1.0000
5:143282723:GAA:G	acceptor_gain	1.0000
5:143282724:AA:A	acceptor_gain	1.0000
5:143282726:C:CC	acceptor_gain	1.0000
5:143284682:T:TA	donor_gain	1.0000
5:143284683:C:A	donor_gain	1.0000
5:143298666:A:AC	donor_gain	1.0000
5:143298666:ACT:A	donor_gain	1.0000
5:143298667:C:CA	donor_gain	1.0000
5:143298667:CT:C	donor_gain	1.0000
5:143298667:CTC:C	donor_gain	1.0000
5:143298667:CTCA:C	donor_gain	1.0000
5:143300764:C:CC	acceptor_gain	1.0000
5:143310091:TATTA:T	donor_loss	1.0000
5:143310092:ATTAC:A	donor_loss	1.0000
5:143310093:TTAC:T	donor_loss	1.0000
5:143310094:TA:T	donor_loss	1.0000
5:143310096:C:CT	donor_loss	1.0000
5:143310099:T:A	donor_gain	1.0000
5:143310209:CTGTC:C	acceptor_gain	1.0000

AlphaMissense

5073 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:143281902:A:G	F774S	1.000
5:143282582:C:G	D723H	1.000
5:143282593:G:A	T719I	1.000
5:143282596:A:G	L718P	1.000
5:143282659:A:G	L697P	1.000
5:143295471:A:G	L671P	1.000
5:143298680:A:G	L627P	1.000
5:143298762:A:G	W600R	1.000
5:143298762:A:T	W600R	1.000
5:143298773:A:G	L596P	1.000
5:143298776:A:G	L595P	1.000
5:143298809:A:G	F584S	1.000
5:143300500:C:G	A578P	1.000
5:143300501:C:A	W577C	1.000
5:143300501:C:G	W577C	1.000
5:143300503:A:G	W577R	1.000
5:143300503:A:T	W577R	1.000
5:143300758:T:C	K492E	1.000
5:143310107:C:A	M486I	1.000
5:143310107:C:G	M486I	1.000
5:143310107:C:T	M486I	1.000
5:143310108:A:C	M486R	1.000
5:143310108:A:G	M486T	1.000
5:143310108:A:T	M486K	1.000
5:143310111:C:A	G485V	1.000
5:143310111:C:T	G485E	1.000
5:143310112:C:G	G485R	1.000
5:143310112:C:T	G485R	1.000
5:143310114:G:T	A484D	1.000
5:143310115:C:G	A484P	1.000

dbSNP variants (sampled 300 via entrez): RS1000008906 (5:143323450 C>A), RS1000023621 (5:143420656 G>A), RS1000029185 (5:143419297 G>A), RS1000032853 (5:143369473 C>A), RS1000034122 (5:143425590 A>T), RS1000038888 (5:143339760 T>A), RS1000039401 (5:143289809 A>C), RS1000053290 (5:143335161 A>T), RS1000080092 (5:143338609 A>G), RS1000098622 (5:143283082 C>A,T), RS1000106168 (5:143288439 GTTAA>G,GTTAATTAA), RS1000127061 (5:143378704 G>T), RS1000150480 (5:143372537 A>T), RS1000152295 (5:143295158 A>G,T), RS1000182294 (5:143372238 C>T)

Disease associations

OMIM: gene MIM:138040 | disease phenotypes: MIM:615962, MIM:230200

GenCC curated gene-disease

Disease	Classification	Inheritance
glucocorticoid resistance	Strong	Autosomal dominant

Mondo (3): glucocorticoid resistance (MONDO:0014421), prostate cancer (MONDO:0008315), galactokinase deficiency (MONDO:0009255)

Orphanet (4): Generalized glucocorticoid resistance syndrome (Orphanet:786), Familial prostate cancer (Orphanet:1331), Galactosemia (Orphanet:352), Galactokinase deficiency (Orphanet:79237)

HPO phenotypes

82 total (30 of 82 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000062	Ambiguous genitalia
HP:0000141	Amenorrhea
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000725	Psychotic episodes
HP:0000726	Dementia
HP:0000739	Anxiety
HP:0000789	Infertility
HP:0000798	Oligozoospermia
HP:0000819	Diabetes mellitus
HP:0000822	Hypertension
HP:0000826	Precocious puberty
HP:0000858	Irregular menstruation
HP:0000869	Secondary amenorrhea
HP:0000876	Oligomenorrhea
HP:0000939	Osteoporosis
HP:0000953	Hyperpigmentation of the skin
HP:0000963	Thin skin
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0001007	Hirsutism
HP:0001050	Plethora
HP:0001058	Poor wound healing
HP:0001061	Acne
HP:0001065	Striae distensae
HP:0001123	Visual field defect
HP:0001297	Stroke

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST003542_120	Night sleep phenotypes	4.000000e-07
GCST003542_121	Night sleep phenotypes	6.000000e-06
GCST003542_139	Night sleep phenotypes	8.000000e-06
GCST006061_141	Atrial fibrillation	1.000000e-11
GCST006061_142	Atrial fibrillation	6.000000e-11
GCST006414_140	Atrial fibrillation	2.000000e-17
GCST009306_8	Spatial processing	4.000000e-06
GCST010321_138	PR interval	3.000000e-10
GCST012227_193	Hip circumference adjusted for BMI	5.000000e-08
GCST012227_194	Hip circumference adjusted for BMI	6.000000e-09
GCST012227_195	Hip circumference adjusted for BMI	1.000000e-09
GCST90000025_21	Appendicular lean mass	7.000000e-12
GCST90002389_266	Lymphocyte percentage of white cells	7.000000e-13
GCST90002399_426	Neutrophil percentage of white cells	2.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0008354	cognitive function measurement
EFO:0004462	PR interval
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C564221	Glucocorticoid Receptor Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2034 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

162 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 863,411 (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
CHEMBL103	PROGESTERONE	4	162,141
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1064	SIMVASTATIN	4	123,163
CHEMBL1082407	ENZALUTAMIDE	4	9,652
CHEMBL1095097	EPLERENONE	4	13,067
CHEMBL110691	CHLORMADINONE ACETATE	4	9,747
CHEMBL1117	IDARUBICIN	4	136,065
CHEMBL1159650	CLOBETASOL PROPIONATE	4	30,865
CHEMBL1161	MOMETASONE FUROATE	4	25,884
CHEMBL1162	NORETHINDRONE	4	91,150
CHEMBL1170	TESTOSTERONE PROPIONATE	4	17,619
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1200374	EXEMESTANE	4	72,530
CHEMBL1200384	BETAMETHASONE DIPROPIONATE	4	12,700
CHEMBL1200386	PREDNICARBATE	4	12,068
CHEMBL1200438	TIOCONAZOLE	4	15,162
CHEMBL1200500	BECLOMETHASONE DIPROPIONATE	4	29,239
CHEMBL1200545	DIFLORASONE DIACETATE	4	20,278
CHEMBL1200585	OXYMETHOLONE	4
CHEMBL1200592	DESOXYCORTICOSTERONE PIVALATE	4
CHEMBL1200600	FLUOROMETHOLONE	4
CHEMBL1200617	RIMEXOLONE	4
CHEMBL1200732	AMCINONIDE	4
CHEMBL1200845	HALCINONIDE	4
CHEMBL1200848	HYDROXYPROGESTERONE CAPROATE	4
CHEMBL1200865	LOTEPREDNOL ETABONATE	4
CHEMBL1200934	NORGESTIMATE	4
CHEMBL1200989	ALCLOMETASONE DIPROPIONATE	4

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

PharmGKB variants

14 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs852977	NR3C1		0.00	0
rs10482633	NR3C1		0.00	0
rs33389	NR3C1		0.00	0
rs33388	NR3C1		0.00	0
rs6196	NR3C1		0.00	0
rs258751	NR3C1		0.00	0
rs10052957	NR3C1		0.00	0
rs41423247	NR3C1		0.00	0
rs6190	NR3C1		0.00	0
rs10482672	NR3C1		0.00	0
rs2963155	NR3C1		0.00	0
rs9324918	NR3C1		0.00	0
rs6198	NR3C1		0.00	0
rs10482634	NR3C1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: nhr — 3C. 3-Ketosteroid receptors

Most potent curated ligand interactions (42 total), top 25:

Ligand	Action	Affinity	Parameter
AZD5423	Antagonist	10.31	pIC50
dazucorilant	Antagonist	9.55	pKi
mifepristone	Antagonist	9.4	pKd
clobetasol propionate	Agonist	9.18	pKi
C108297	Agonist	9.15	pKi
compound 17 [PMID: 29741897]	Agonist	9.12	pKi
velsecorat	Agonist	9.05	pEC50
dexamethasone	Agonist	9.0	pIC50
desoximetasone	Agonist	8.93	pKi
AZD2906	Agonist	8.89	pEC50
dagrocorat	Partial agonist	8.88	pIC50
fluorometholone	Agonist	8.8	pKi
flunisolide	Agonist	8.62	pKi
diflorasone diacetate	Agonist	8.54	pKi
ABBV-3373	Agonist	8.52	pIC50
fluocinolone acetonide	Agonist	8.5	pIC50
GSK866	Agonist	8.5	pIC50
beclometasone	Full agonist	8.43	pKi
methylprednisolone	Agonist	8.3	pKi
ORG 214007-0	Partial agonist	8.29	pEC50
fluocinonide	Agonist	8.28	pIC50
ORIC-101	Antagonist	8.25	pIC50
triamcinolone acetonide	Agonist	8.2	pIC50
CpdA (parent molecule)	Agonist	8.19	pIC50
prednisolone	Full agonist	8.15	pIC50

Binding affinities (BindingDB)

810 measured of 1075 human assays (1077 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
dexamethasone (tetramethyl-rhodamine conjugated )	EC50	0.2 nM
2-{[(18Z)-13-hydroxy-12-methoxy-3,5,5-trimethyl-17-oxa-6-azatetracyclo[8.8.0.0^{2,7}.0^{11,16}]octadeca-1(10),2(7),3,8,11,13,15-heptaen-18-ylidene]methyl}thiophene-3-carbonitrile	EC50	0.2 nM
(18Z)-12-methoxy-3,5,5-trimethyl-18-({3-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]thiophen-2-yl}methylidene)-17-oxa-6-azatetracyclo[8.8.0.0^{2,7}.0^{11,16}]octadeca-1(10),2(7),3,8,11,13,15-heptaen-13-ol	IC50	0.2 nM
Flovent hfa	KI	0.238 nM
N-carbamoyl-2-[(5S)-9-fluoro-2-(4-propan-2-yloxyphenyl)-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	0.25 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
(18Z)-12-methoxy-3,5,5-trimethyl-18-{[3-(piperidin-1-ylcarbonyl)thiophen-2-yl]methylidene}-17-oxa-6-azatetracyclo[8.8.0.0^{2,7}.0^{11,16}]octadeca-1(10),2(7),3,8,11,13,15-heptaen-13-ol	EC50	0.3 nM
1-(2-{[(18Z)-13-hydroxy-12-methoxy-3,5,5-trimethyl-17-oxa-6-azatetracyclo[8.8.0.0^{2,7}.0^{11,16}]octadeca-1(10),2(7),3,8,11,13,15-heptaen-18-ylidene]methyl}thiophen-3-yl)ethan-1-one	IC50	0.3 nM
desisobutyryl-ciclesonide	KI	0.31 nM
N-carbamoyl-2-[(5S)-9-fluoro-2-[4-(2-hydroxypropan-2-yl)phenyl]-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	0.32 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
(4bS,7R,8aR)-4b-benzyl-N-(3,5-dimethylpyrazin-2-yl)-7-hydroxy-7-(trifluoromethyl)-5,6,8,8a,9,10-hexahydrophenanthrene-2-carboxamide	IC50	0.35 nM	US-8901310: Tricyclic compounds, compositions, and methods
(18Z)-18-({3-[(1E)-1-(ethoxyimino)ethyl]thiophen-2-yl}methylidene)-12-methoxy-3,5,5-trimethyl-17-oxa-6-azatetracyclo[8.8.0.0^{2,7}.0^{11,16}]octadeca-1(10),2(7),3,8,11,13,15-heptaen-13-ol	EC50	0.4 nM
(18Z)-18-[(3-cyclohexanecarbonylthiophen-2-yl)methylidene]-12-methoxy-3,5,5-trimethyl-17-oxa-6-azatetracyclo[8.8.0.0^{2,7}.0^{11,16}]octadeca-1(10),2(7),3,8,11,13,15-heptaen-13-ol	EC50	0.4 nM
N-carbamoyl-2-[(5S)-9-fluoro-2-(3-fluoro-4-propan-2-yloxyphenyl)-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	0.4 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
N-carbamoyl-2-[(5S)-2-(4-ethylsulfonylphenyl)-9-fluoro-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	0.43 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
(18Z)-12-methoxy-3,5,5-trimethyl-18-[(3-{[(2,2,2-trifluoroethyl)amino]methyl}thiophen-2-yl)methylidene]-17-oxa-6-azatetracyclo[8.8.0.0^{2,7}.0^{11,16}]octadeca-1(10),2(7),3,8,11,13,15-heptaen-13-ol	EC50	0.5 nM
N-carbamoyl-2-methyl-2-[(5S)-2-(6-propan-2-yloxy-3-pyridinyl)-5H-chromeno[2,3-b]pyridin-5-yl]propanamide	KI	0.5 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
N-carbamoyl-2-methyl-2-[(5S)-2-(4-propan-2-ylsulfonylphenyl)-5H-chromeno[2,3-b]pyridin-5-yl]propanamide	KI	0.58 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
N-carbamoyl-2-[(5S)-9-fluoro-2-(4-methylsulfonylphenyl)-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	0.59 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
(18Z)-12-methoxy-3,5,5-trimethyl-18-({3-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]thiophen-2-yl}methylidene)-17-oxa-6-azatetracyclo[8.8.0.0^{2,7}.0^{11,16}]octadeca-1(10),2(7),3,8,11,13,15-heptaen-13-ol	IC50	0.6 nM
(18Z)-18-{[3-(1-hydroxypentyl)thiophen-2-yl]methylidene}-12-methoxy-3,5,5-trimethyl-17-oxa-6-azatetracyclo[8.8.0.0^{2,7}.0^{11,16}]octadeca-1(10),2(7),3,8,11,13,15-heptaen-13-ol	EC50	0.6 nM
2-[(5S)-9-fluoro-2-(6-propan-2-yloxy-3-pyridinyl)-5H-chromeno[2,3-b]pyridin-5-yl]-N-[(4-methoxyphenyl)methylcarbamoyl]-2-methylpropanamide	KI	0.63 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-[(1R,2S)-2-hydroxycyclopentyl]benzamide	IC50	0.647 nM	US-8916600: Phenyl and benzodioxinyl substituted indazoles derivatives
(S)-5-(2-(1H-Imidazo[4,5-b]pyrazin-2-yl)propan-2-yl)-2-(4-ethoxyphenyl)-9-fluoro-5H-chromeno[2,3-b]pyridine	KI	0.66 nM	US-9796720: Imidazole-derived modulators of the glucocorticoid receptor
3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-(1,1-dioxothiolan-3-yl)benzamide	IC50	0.663 nM	US-8916600: Phenyl and benzodioxinyl substituted indazoles derivatives
(S)-5-(2-(1H-Imidazo[4,5-b]pyrazin-2-yl)propan-2-yl)-9-fluoro-2-(3-fluoro-4-isopropoxyphenyl)-5H-chromeno[2,3-b]pyridine	KI	0.67 nM	US-9796720: Imidazole-derived modulators of the glucocorticoid receptor
N-carbamoyl-2-[(5S)-9-fluoro-2-[4-(pyrrolidine-1-carbonyl)phenyl]-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	0.72 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
(S)-2-(9-Fluoro-2-(4-(1-methyl-1H-tetrazol-5-yl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanoic acid	KI	0.76 nM	US-9796720: Imidazole-derived modulators of the glucocorticoid receptor
3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-(pyridin-3-ylmethyl)benzamide	IC50	0.767 nM	US-8916600: Phenyl and benzodioxinyl substituted indazoles derivatives
3-[5-[(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-(2,2-difluoropropanoylamino)propoxy]indazol-1-yl]-N-cyclopentylbenzamide	IC50	0.796 nM	US-8916600: Phenyl and benzodioxinyl substituted indazoles derivatives
(1S)-1-[(4aR,5S)-1-(4-fluorophenyl)-4a-methyl-1H,4H,4aH,5H,6H,7H,8H-cyclohexa[f]indazol-5-yl]-1-(thiophen-3-yl)ethan-1-ol	IC50	0.8 nM
N-carbamoyl-2-methyl-2-[(5S)-2-(4-propan-2-yloxyphenyl)-5H-chromeno[2,3-b]pyridin-5-yl]propanamide	KI	0.8 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
3-[5-[(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-(2,2-difluoropropanoylamino)propoxy]indazol-1-yl]-N-(pyridin-3-ylmethyl)benzamide	IC50	0.817 nM	US-8916600: Phenyl and benzodioxinyl substituted indazoles derivatives
N-carbamoyl-2-[(5S)-9-fluoro-2-[4-(tetrazol-1-yl)phenyl]-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	0.82 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
(S)-5-(2-(1H-Imidazo[4,5-b]pyrazin-2-yl)propan-2-yl)-2-(4-tert-butoxyphenyl)-9-fluoro-5H-chromeno[2,3-b]pyridine	KI	0.82 nM	US-9796720: Imidazole-derived modulators of the glucocorticoid receptor
(15R)-8-cyano-15-methyl-N-(1,3-thiazol-2-yl)tetracyclo[6.6.2.0^{2,7}.0^{9,14}]hexadeca-2,4,6,9(14),10,12-hexaene-15-carboxamide	KI	0.9 nM
2-[(5S)-2-(4-butylphenyl)-9-fluoro-5H-chromeno[2,3-b]pyridin-5-yl]-N-carbamoyl-2-methylpropanamide	KI	0.91 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-[(3R)-oxolan-3-yl]benzamide	IC50	0.913 nM	US-8916600: Phenyl and benzodioxinyl substituted indazoles derivatives
N-carbamoyl-2-[(5S)-9-fluoro-2-(4-phenylphenyl)-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	0.92 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
N-carbamoyl-2-[(5S)-2-(4-ethylsulfonylphenyl)-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	0.93 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
2-[(5S)-2-[4-(azetidine-1-carbonyl)phenyl]-9-fluoro-5H-chromeno[2,3-b]pyridin-5-yl]-N-carbamoyl-2-methylpropanamide	KI	0.93 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
3-[5-[(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-(2,2-difluoropropanoylamino)propoxy]indazol-1-yl]-N-benzylbenzamide	IC50	0.996 nM	US-8916600: Phenyl and benzodioxinyl substituted indazoles derivatives
(18Z)-18-({3-[(2-hydroxyethoxy)methyl]thiophen-2-yl}methylidene)-12-methoxy-3,5,5-trimethyl-17-oxa-6-azatetracyclo[8.8.0.0^{2,7}.0^{11,16}]octadeca-1(10),2(7),3,8,11,13,15-heptaen-13-ol	IC50	1 nM
(R)-(4aR,5S)-1-(4-fluorophenyl)-4a-methyl-1H,4H,4aH,5H,6H,7H,8H-cyclohexa[f]indazol-5-ylmethanol	EC50	1 nM
3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-[(3S)-oxolan-3-yl]benzamide	IC50	1.08 nM	US-8916600: Phenyl and benzodioxinyl substituted indazoles derivatives
3-[5-[(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-(2,2-difluoropropanoylamino)propoxy]indazol-1-yl]-N-[(3S)-oxolan-3-yl]benzamide	IC50	1.09 nM	US-8916600: Phenyl and benzodioxinyl substituted indazoles derivatives
N-carbamoyl-2-[(5S)-2-[4-(3,3-difluoropyrrolidine-1-carbonyl)-3-fluorophenyl]-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	1.09 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
(1S)-1-[(4aR,5S)-1-(4-fluorophenyl)-4a-methyl-1H,4H,4aH,5H,6H,7H,8H-cyclohexa[f]indazol-5-yl]pent-4-en-1-ol	IC50	1.1 nM
N-carbamoyl-2-[(5S)-9-fluoro-2-(6-morpholin-4-yl-3-pyridinyl)-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	1.11 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
2-[(5S)-9-fluoro-2-[4-(piperidine-1-carbonyl)phenyl]-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	1.11 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor
N-carbamoyl-2-[(5S)-9-fluoro-2-[6-(propan-2-ylamino)-3-pyridinyl]-5H-chromeno[2,3-b]pyridin-5-yl]-2-methylpropanamide	KI	1.13 nM	US-9593113: Imide and acylurea derivatives as modulators of the glucocorticoid receptor

ChEMBL bioactivities

6072 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	IC50	0.02	nM	CHEMBL4104286
10.70	EC50	0.02	nM	GLUCAGON
10.54	IC50	0.029	nM	CHEMBL4061359
10.52	IC50	0.03	nM	CHEMBL3911831
10.52	IC50	0.03	nM	CHEMBL3895181
10.52	EC50	0.03	nM	GLUCAGON
10.49	IC50	0.032	nM	CHEMBL4086388
10.43	IC50	0.037	nM	CHEMBL3666813
10.40	IC50	0.04	nM	CHEMBL3973775
10.40	IC50	0.04	nM	CHEMBL3902818
10.40	EC50	0.04	nM	CHEMBL3964460
10.40	IC50	0.04	nM	FLUTICASONE PROPIONATE
10.40	EC50	0.04	nM	CHEMBL5080959
10.40	IC50	0.03981	nM	FLUTICASONE FUROATE
10.36	IC50	0.044	nM	FLUTICASONE PROPIONATE
10.31	IC50	0.049	nM	AZD-5423
10.30	IC50	0.05	nM	CHEMBL3920760
10.30	EC50	0.05	nM	CHEMBL3981243
10.29	IC50	0.051	nM	CHEMBL3666806
10.25	IC50	0.056	nM	VELSECORAT
10.21	IC50	0.062	nM	CHEMBL3666814
10.18	IC50	0.066	nM	CHEMBL4094154
10.15	IC50	0.07	nM	CHEMBL3933702
10.14	IC50	0.073	nM	CHEMBL4061359
10.12	IC50	0.075	nM	FLUTICASONE PROPIONATE
10.10	IC50	0.08	nM	CHEMBL3901719
10.10	IC50	0.08	nM	CHEMBL4104286
10.10	Ki	0.08	nM	CHEMBL4081121
10.10	IC50	0.07943	nM	CHEMBL551816
10.10	IC50	0.07943	nM	CHEMBL1668063
10.05	IC50	0.09	nM	CHEMBL3940724
10.05	IC50	0.09	nM	CHEMBL3960682
10.05	Ki	0.09	nM	MIFEPRISTONE
10.00	EC50	0.1	nM	CHEMBL2426624
10.00	Ki	0.1	nM	MIFEPRISTONE
10.00	Ki	0.1	nM	CHEMBL3736358
10.00	IC50	0.1	nM	CHEMBL222900
10.00	IC50	0.101	nM	CHEMBL4086388
10.00	EC50	0.1	nM	DEXAMETHASONE
10.00	EC50	0.1	nM	CHEMBL397920
10.00	IC50	0.1	nM	CHEMBL3706941
10.00	ED50	0.1	nM	DEXAMETHASONE
10.00	Ki	0.1	nM	CHEMBL77779
10.00	IC50	0.1	nM	CHEMBL5927561
10.00	Ki	0.1	nM	CHEMBL78704
9.96	Ki	0.11	nM	CHEMBL409123
9.96	EC50	0.11	nM	CHEMBL3895181
9.92	IC50	0.12	nM	CHEMBL4070346
9.92	Ki	0.12	nM	CHEMBL4088286
9.90	IC50	0.1259	nM	CHEMBL551816

PubChem BioAssay actives

2538 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
(8S,9S,11S,13S,14S,17S)-17-hydroxy-13-methyl-N-(2-methyl-3-pyridinyl)-11-prop-2-enoxy-17-prop-1-ynyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3-carboxamide	1332263: Antagonist activity at GR in human HepG2 cells assessed as inhibition of protein mediated-transcriptional activity by MMTV-promoter driven luciferase reporter gene assay	ic50	<0.0001	uM
(8S,9S,11S,13S,14S,17S)-17-hydroxy-11-methoxy-13-methyl-N-(2-methyl-3-pyridinyl)-17-prop-1-ynyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3-carboxamide	1332262: Agonist activity at GR in human HepG2 cells assessed as protein mediated-transcriptional activity by MMTV-promoter driven luciferase reporter gene assay	ec50	<0.0001	uM
(3S)-3-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[2-aminoethylsulfonyl-[2-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-methylpentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoic acid	1832719: Activation of human GCCR expressed in human CHO-K1 cell lines assessed as intracellular cAMP generation incubated for 30 mins measured by HTRF assay	ec50	<0.0001	uM
2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]acetamide	1476001: Transrepression of glucocorticoid receptor in PMA-stimulated human ChaGoK1 cells expressing TRE-LacZ construct assessed as inhibition of AP-1 mediated TRE-LacZ activity after 24 hrs by beta-galactosidase reporter gene assay	ic50	<0.0001	uM
2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]acetamide	1328538: Agonist activity at glucocorticoid receptor in human ChaGoK1 cells assessed as inhibition of AP1-mediated transcriptional activity by measuring reduction in PMA-stimulated TRE-LacZ activity after 24 hrs in presence of MUG by fluorometric assay	ic50	<0.0001	uM
2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-naphthalen-2-ylpropan-2-yl]acetamide	1328538: Agonist activity at glucocorticoid receptor in human ChaGoK1 cells assessed as inhibition of AP1-mediated transcriptional activity by measuring reduction in PMA-stimulated TRE-LacZ activity after 24 hrs in presence of MUG by fluorometric assay	ic50	<0.0001	uM
(8S,9S,11S,13S,14S,17S)-11-[(4-chlorophenyl)methoxy]-17-hydroxy-13-methyl-N-(2-methyl-3-pyridinyl)-17-prop-1-ynyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3-carboxamide	1332263: Antagonist activity at GR in human HepG2 cells assessed as inhibition of protein mediated-transcriptional activity by MMTV-promoter driven luciferase reporter gene assay	ic50	0.0001	uM
N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenylpropan-2-yl]-5-methyl-1,2,4-oxadiazole-3-carboxamide	1328538: Agonist activity at glucocorticoid receptor in human ChaGoK1 cells assessed as inhibition of AP1-mediated transcriptional activity by measuring reduction in PMA-stimulated TRE-LacZ activity after 24 hrs in presence of MUG by fluorometric assay	ic50	0.0001	uM
(8S,9S,11S,13S,14S,17S)-11-ethoxy-17-hydroxy-13-methyl-N-(2-methyl-3-pyridinyl)-17-prop-1-ynyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3-carboxamide	1332262: Agonist activity at GR in human HepG2 cells assessed as protein mediated-transcriptional activity by MMTV-promoter driven luciferase reporter gene assay	ec50	0.0001	uM
(2R)-1-[3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]benzoyl]pyrrolidine-2-carboxamide	1476001: Transrepression of glucocorticoid receptor in PMA-stimulated human ChaGoK1 cells expressing TRE-LacZ construct assessed as inhibition of AP-1 mediated TRE-LacZ activity after 24 hrs by beta-galactosidase reporter gene assay	ic50	0.0001	uM
N-[(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,2-difluoropropanamide	1476001: Transrepression of glucocorticoid receptor in PMA-stimulated human ChaGoK1 cells expressing TRE-LacZ construct assessed as inhibition of AP-1 mediated TRE-LacZ activity after 24 hrs by beta-galactosidase reporter gene assay	ic50	0.0001	uM
(2R)-1-[3-[5-[(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-(2,2-difluoropropanoylamino)propoxy]indazol-1-yl]benzoyl]pyrrolidine-2-carboxamide	1476001: Transrepression of glucocorticoid receptor in PMA-stimulated human ChaGoK1 cells expressing TRE-LacZ construct assessed as inhibition of AP-1 mediated TRE-LacZ activity after 24 hrs by beta-galactosidase reporter gene assay	ic50	0.0001	uM
(5Z)-10-methoxy-5-[[3-[(E)-N-methoxy-C-methylcarbonimidoyl]thiophen-2-yl]methylidene]-2,2,4-trimethyl-1H-chromeno[3,4-f]quinolin-9-ol	297837: Agonist activity at human GR expressed in CV1 cells by GRE activation assay	ec50	0.0001	uM
N-ethyl-2-fluoro-N-[3,3,3-trifluoro-2-[[[1-(4-fluorophenyl)indazol-4-yl]amino]methyl]-2-hydroxypropyl]benzamide	429130: Agonist activity at GR in human A549 cells by NF-kappaB transrepression assay	ic50	0.0001	uM
2,6-dichloro-N-ethyl-N-[3,3,3-trifluoro-2-[[[1-(4-fluorophenyl)indazol-4-yl]amino]methyl]-2-hydroxypropyl]benzamide	429130: Agonist activity at GR in human A549 cells by NF-kappaB transrepression assay	ic50	0.0001	uM
N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,2-dimethylpropanamide	1328538: Agonist activity at glucocorticoid receptor in human ChaGoK1 cells assessed as inhibition of AP1-mediated transcriptional activity by measuring reduction in PMA-stimulated TRE-LacZ activity after 24 hrs in presence of MUG by fluorometric assay	ic50	0.0001	uM
2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenylpropan-2-yl]acetamide	1328538: Agonist activity at glucocorticoid receptor in human ChaGoK1 cells assessed as inhibition of AP1-mediated transcriptional activity by measuring reduction in PMA-stimulated TRE-LacZ activity after 24 hrs in presence of MUG by fluorometric assay	ic50	0.0001	uM
N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]-2,2-dimethylpropanamide	1328538: Agonist activity at glucocorticoid receptor in human ChaGoK1 cells assessed as inhibition of AP1-mediated transcriptional activity by measuring reduction in PMA-stimulated TRE-LacZ activity after 24 hrs in presence of MUG by fluorometric assay	ic50	0.0001	uM
(5Z)-10-methoxy-5-[[3-(methoxymethyl)thiophen-2-yl]methylidene]-2,2,4-trimethyl-1H-chromeno[3,4-f]quinolin-9-ol	1797744: Competitive Ligand Binding Assay, GR-Mediated Agonist Activity Assay, and IL-6 Repression Assay from Article 10.1021/jm070370z: “Synthesis and characterization of nonsteroidal glucocorticoid receptor modulators for multiple myeloma.”	ki	0.0002	uM
(5Z)-5-[[3-(hydroxymethyl)thiophen-2-yl]methylidene]-10-methoxy-2,2,4-trimethyl-1H-chromeno[3,4-f]quinolin-9-ol	297837: Agonist activity at human GR expressed in CV1 cells by GRE activation assay	ec50	0.0002	uM
(5Z)-10-methoxy-2,2,4-trimethyl-5-[(3-methylphenyl)methylidene]-1H-chromeno[3,4-f]quinolin-9-ol	299614: Antagonist activity at GR assessed as inhibition of dexamethasone-induced GRE activation	ic50	0.0002	uM
5-chloro-6-(1H-indol-7-yl)-2,2,4,8-tetramethyl-3,4-dihydro-1H-quinolin-3-ol	552806: Transrepression activity at glucocorticoid receptor in TNFalpha/IL1beta-stimulated human HepG2 cells assessed as inhibition of NFkappaB-dependent E-selectin transcription by luciferase reporter gene assay	ic50	0.0002	uM
(5Z)-5-[(6-fluoro-4H-1,3-benzodioxin-8-yl)methylidene]-10-methoxy-2,2,4-trimethyl-1H-chromeno[3,4-f]quinolin-9-ol	299612: Agonist activity at GR by GRE activation assay	ec50	0.0002	uM
(5Z)-10-methoxy-2,2,4-trimethyl-5-[[3-(2,2,2-trifluoro-1-hydroxyethyl)thiophen-2-yl]methylidene]-1H-chromeno[3,4-f]quinolin-9-ol	297856: Antagonist activity at human GR expressed in CV1 cells by GRE activation assay	ec50	0.0002	uM
(2R,3S)-3-(2-chloro-3-fluoro-4-methoxyphenyl)-2-(ethylsulfanylmethyl)-1,1,1-trifluoro-3-[(2-methylquinolin-5-yl)amino]propan-2-ol	1460351: Transrepression activity at glucocorticoid receptorin human HeLa cells assessed as inhibition of TPA-induced collagenase promoter activity by luciferase reporter gene assay	ic50	0.0002	uM
N-[(1R,2S)-1-(4H-1,3-benzodioxin-6-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2,2-difluoropropanamide	1476001: Transrepression of glucocorticoid receptor in PMA-stimulated human ChaGoK1 cells expressing TRE-LacZ construct assessed as inhibition of AP-1 mediated TRE-LacZ activity after 24 hrs by beta-galactosidase reporter gene assay	ic50	0.0002	uM
[2-[(Z)-(9-hydroxy-10-methoxy-2,2,4-trimethyl-1H-chromeno[3,4-f]quinolin-5-ylidene)methyl]thiophen-3-yl]-piperidin-1-ylmethanone	299612: Agonist activity at GR by GRE activation assay	ec50	0.0002	uM
2-[(Z)-(9-hydroxy-10-methoxy-2,2,4-trimethyl-1H-chromeno[3,4-f]quinolin-5-ylidene)methyl]thiophene-3-carbonitrile	297837: Agonist activity at human GR expressed in CV1 cells by GRE activation assay	ec50	0.0002	uM
(5Z)-10-methoxy-2,2,4-trimethyl-5-[[3-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]thiophen-2-yl]methylidene]-1H-chromeno[3,4-f]quinolin-9-ol	1797746: GR-Mediated Antagonist Activity Assay and IL-6 Repression Assay from Article 10.1021/jm070370z: “Synthesis and characterization of nonsteroidal glucocorticoid receptor modulators for multiple myeloma.”	ic50	0.0002	uM
N-[(1R,2S)-1-(4-ethylphenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]oxypropan-2-yl]-2-hydroxyacetamide	1328538: Agonist activity at glucocorticoid receptor in human ChaGoK1 cells assessed as inhibition of AP1-mediated transcriptional activity by measuring reduction in PMA-stimulated TRE-LacZ activity after 24 hrs in presence of MUG by fluorometric assay	ic50	0.0002	uM
N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(6-methoxy-3-pyridinyl)propan-2-yl]cyclopropanecarboxamide	1380136: Transrepression activity at glucocorticoid receptor (unknown origin) expressed in human ChaGoK1 cells assessed as inhibition of PMA-stimulated gene expression incubated for 24 hrs by beta-galactosidase reporter gene assay	ic50	0.0002	uM
1-[2-[(Z)-(9-hydroxy-10-methoxy-2,2,4-trimethyl-1H-chromeno[3,4-f]quinolin-5-ylidene)methyl]thiophen-3-yl]ethanone	1797745: GR-Mediated Agonist Activity Assay and IL-6 Repression Assay from Article 10.1021/jm070370z: “Synthesis and characterization of nonsteroidal glucocorticoid receptor modulators for multiple myeloma.”	ic50	0.0003	uM
5-chloro-6-(1H-indol-7-yl)-2,2,4,8-tetramethyl-3,4-dihydro-1H-quinoline	331514: Displacement of radiolabeled Dexamethasone from glucocorticoid receptor	ki	0.0003	uM
2,2-difluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-3-methyl-1-phenylbutan-2-yl]propanamide	1380136: Transrepression activity at glucocorticoid receptor (unknown origin) expressed in human ChaGoK1 cells assessed as inhibition of PMA-stimulated gene expression incubated for 24 hrs by beta-galactosidase reporter gene assay	ic50	0.0003	uM
N-[3-[(1E)-1-(6H-benzo[c][1]benzoxepin-11-ylidene)ethyl]phenyl]methanesulfonamide	1071638: Displacement of [3H]-dexamethasone from human glucocorticoid receptor expressed in HEK293 cells	ki	0.0003	uM
N-ethyl-2-methyl-N-[3,3,3-trifluoro-2-[[[1-(4-fluorophenyl)indazol-4-yl]amino]methyl]-2-hydroxypropyl]benzamide	429130: Agonist activity at GR in human A549 cells by NF-kappaB transrepression assay	ic50	0.0003	uM
2-[(9S)-3-hydroxy-9H-xanthen-9-yl]-2-methyl-N-(1,3-thiazol-2-yl)propanamide	604795: Displacement of GS-red from GRapha by fluorescence polarization assay	ki	0.0003	uM
N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methoxyphenyl)propan-2-yl]-2,2-dimethylpropanamide	1328538: Agonist activity at glucocorticoid receptor in human ChaGoK1 cells assessed as inhibition of AP1-mediated transcriptional activity by measuring reduction in PMA-stimulated TRE-LacZ activity after 24 hrs in presence of MUG by fluorometric assay	ic50	0.0003	uM
(5Z)-5-[[3-[(E)-N-ethoxy-C-methylcarbonimidoyl]thiophen-2-yl]methylidene]-10-methoxy-2,2,4-trimethyl-1H-chromeno[3,4-f]quinolin-9-ol	297837: Agonist activity at human GR expressed in CV1 cells by GRE activation assay	ec50	0.0004	uM
(5Z)-5-[(4-hydroxyphenyl)methylidene]-10-methoxy-2,2,4-trimethyl-1H-chromeno[3,4-f]quinolin-9-ol	299614: Antagonist activity at GR assessed as inhibition of dexamethasone-induced GRE activation	ic50	0.0004	uM
(5Z)-5-[[4-fluoro-2-(methoxymethoxymethyl)phenyl]methylidene]-10-methoxy-2,2,4-trimethyl-1H-chromeno[3,4-f]quinolin-9-ol	299614: Antagonist activity at GR assessed as inhibition of dexamethasone-induced GRE activation	ic50	0.0004	uM
1-[(1S,2R,13S,14S,17R,18S,20S)-7-(4-fluorophenyl)-17,20-dihydroxy-2,18-dimethyl-6,7-diazapentacyclo[11.7.0.02,10.04,8.014,18]icosa-4(8),5,9-trien-17-yl]-2-hydroxyethanone	659496: Transrepression activity at glucocorticoid receptor in human H292 cells assessed as inhibition of TNF-induced IL8 production	ic50	0.0004	uM
(8S,9S,11S,13S,14S,17S)-17-hydroxy-13-methyl-N-(2-methyl-3-pyridinyl)-11-phenylmethoxy-17-prop-1-ynyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3-carboxamide	1332263: Antagonist activity at GR in human HepG2 cells assessed as inhibition of protein mediated-transcriptional activity by MMTV-promoter driven luciferase reporter gene assay	ic50	0.0004	uM
(E)-N-ethoxy-5,7-difluoro-6-(1H-indol-7-yl)-2,2-dimethyl-1,3-dihydroquinolin-4-imine	589652: Displacement of radiolabeled Dexamethasone from glucocorticoid receptor expressed in baculovirus	ki	0.0004	uM
2,2,2-trifluoro-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-3-methyl-1-phenylbutan-2-yl]acetamide	1380136: Transrepression activity at glucocorticoid receptor (unknown origin) expressed in human ChaGoK1 cells assessed as inhibition of PMA-stimulated gene expression incubated for 24 hrs by beta-galactosidase reporter gene assay	ic50	0.0004	uM
(1’S,5R)-1-(4-fluorophenyl)-1’-phenylspiro[4H-indazole-5,2’-cyclohexane]-1’-ol	1530700: Displacement of [3H]dexamethasone from GR in human IM9 cells after 6 hrs by scintillation counting method	ic50	0.0004	uM
2-[[1-(2-chloro-5-fluorophenyl)cyclobutyl]methyl]-3,3,3-trifluoro-2-hydroxy-N-(4-methyl-1-oxo-2,3-benzoxazin-6-yl)propanamide	1203066: Binding affinity to human GR	ic50	0.0004	uM
(3S)-3-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-5-amino-2-[[2-[[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]-2-methylpropanoyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[2-aminoethylsulfonyl-[2-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-methylpentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoic acid	1832719: Activation of human GCCR expressed in human CHO-K1 cell lines assessed as intracellular cAMP generation incubated for 30 mins measured by HTRF assay	ec50	0.0004	uM
(3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-5-amino-5-oxopentanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]-6-aminohexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]-5-amino-5-oxopentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[2-aminoethylsulfonyl-[2-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-methylpentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoic acid	1832719: Activation of human GCCR expressed in human CHO-K1 cell lines assessed as intracellular cAMP generation incubated for 30 mins measured by HTRF assay	ec50	0.0004	uM
5-amino-N-[(2S)-2-[[ethyl-(2-ethyl-6-methylbenzoyl)amino]methyl]-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)pyrazole-4-carboxamide	2110358: Agonist activity at glucocorticoid receptor (unknown origin) incubated for 24 hrs by cell based microplate analysis	ec50	0.0004	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Dexamethasone	affects binding, decreases expression, affects localization, decreases reaction, increases activity (+14 more)	76
Hydrocortisone	decreases reaction, affects cotreatment, decreases expression, affects reaction, increases activity (+7 more)	30
Mifepristone	decreases activity, decreases reaction, decreases response to substance, affects localization, increases expression (+5 more)	23
bisphenol A	affects binding, decreases reaction, increases activity, decreases activity, decreases expression (+1 more)	9
Tetrachlorodibenzodioxin	increases reaction, increases expression, decreases expression, decreases reaction, affects cotreatment (+1 more)	9
Beclomethasone	affects localization, increases activity, affects binding, affects cotreatment, increases expression	8
Valproic Acid	decreases methylation, affects cotreatment, increases expression	8
Prednisolone	affects binding, affects response to substance, decreases reaction, increases activity	6
Budesonide	decreases reaction, increases activity, affects reaction, increases expression, affects binding (+1 more)	6
Fluticasone	affects cotreatment, increases reaction, affects localization, increases activity, affects binding	5
Estradiol	affects binding, affects cotreatment, decreases reaction, increases expression, decreases expression (+1 more)	5
Glucocorticoids	decreases response to substance, increases response to substance, affects response to substance, increases expression, increases activity	5
Progesterone	increases activity, increases phosphorylation, affects cotreatment, increases expression, decreases expression (+3 more)	5
arsenite	affects activity, increases response to substance, affects binding, decreases activity, decreases expression (+4 more)	4
bisphenol AF	affects binding, decreases reaction, increases activity	4
Salmeterol Xinafoate	increases reaction, affects cotreatment, affects localization, increases activity, affects binding	4
Benzo(a)pyrene	affects activity, affects expression, affects reaction, decreases methylation, increases expression	4
Betamethasone	affects binding, increases activity, decreases reaction	4
Triamcinolone	decreases reaction, increases activity, affects binding	4
Triamcinolone Acetonide	affects localization, decreases secretion, decreases expression, affects binding	4
trichostatin A	decreases expression, increases expression, affects expression	3
bisphenol B	affects binding, decreases reaction, increases activity	3
bisphenol Z	affects binding, decreases reaction, increases activity	3
Resveratrol	affects cotreatment, decreases expression, increases expression	3
Acetaminophen	affects activity, affects binding, decreases expression, increases expression	3
Aldosterone	affects binding, increases activity	3
Carbamazepine	affects expression, increases expression, increases reaction	3
Corticosterone	affects binding, increases activity, increases expression	3
Cortisone	decreases reaction, affects binding, increases activity, decreases activity	3
Dichlorodiphenyl Dichloroethylene	decreases reaction, increases activity, increases expression	3

ChEMBL screening assays

1158 unique, capped per target: 865 binding, 263 functional, 28 admet, 2 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1002258	Binding	Inhibition of human glucocorticoid receptor	Discovery of betamethasone 17alpha-carbamates as dissociated glucocorticoid receptor modulators in the rat. — Bioorg Med Chem
CHEMBL1052488	Functional	Agonist activity at glucocorticoid receptor in human MDA-kb2 cells assessed as stimulation of luciferase activity by luciferase reporter gene assay	Effect of flavonoids on androgen and glucocorticoid receptors based on in vitro reporter gene assay. — Bioorg Med Chem Lett
CHEMBL1942837	ADMET	Transactivation of glucocorticoid receptor in human HepG2 cells assessed as induction of TAT measuring degradation of tyrosine to p-hydroxy phenyl pyruvate	Steroidal C-21 heteroaryl thioethers (Part 2): discovery of orally bioavailable selective glucocorticoid receptor modulators (dissociated steroids). — Bioorg Med Chem Lett

Cellosaurus cell lines

36 cell lines: 22 cancer cell line, 9 transformed cell line, 3 embryonic stem cell, 2 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1242	HAL-01	Cancer cell line	Female
CVCL_1631	P30/OHK	Cancer cell line	Female
CVCL_1650	Reh	Cancer cell line	Female
CVCL_3992	KOCL-44	Cancer cell line	Female
CVCL_6866	KOCL-50	Cancer cell line	Female
CVCL_A082	YCUB-2	Cancer cell line	Male
CVCL_A296	UoC-B1	Cancer cell line	Female
CVCL_A441	THP-5	Cancer cell line	Female
CVCL_A4W3	SEES3-1V human NR3C1, clone1	Embryonic stem cell	Male
CVCL_A4W4	SEES3-1V human NR3C1, clone2	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03615742	PHASE4	RECRUITING	Diesel Exhaust Induces Glucocorticoid Resistance
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer