Target Information
| Target General Information | Top | |||||
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| Target ID |
T72841
(Former ID: TTDR00270)
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| Target Name |
Estrogen-related receptor-alpha (ESRRA)
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| Synonyms |
Nuclear receptor subfamily 3 group B member 1; NR3B1; Estrogen-relatedreceptor, alpha; Estrogen-relatedreceptor alpha; Estrogen-related receptor alpha; Estrogen receptor-like 1; ESRL1; ERRalpha; ERR1; ERR-alpha
Click to Show/Hide
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| Gene Name |
ESRRA
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Rheumatoid arthritis [ICD-11: FA20] | |||||
| Function |
Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Induces the expression of PERM1 in the skeletal muscle. Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'.
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| BioChemical Class |
Nuclear hormone receptor
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| UniProt ID | ||||||
| Sequence |
MSSQVVGIEPLYIKAEPASPDSPKGSSETETEPPVALAPGPAPTRCLPGHKEEEDGEGAG
PGEQGGGKLVLSSLPKRLCLVCGDVASGYHYGVASCEACKAFFKRTIQGSIEYSCPASNE CEITKRRRKACQACRFTKCLRVGMLKEGVRLDRVRGGRQKYKRRPEVDPLPFPGPFPAGP LAVAGGPRKTAAPVNALVSHLLVVEPEKLYAMPDPAGPDGHLPAVATLCDLFDREIVVTI SWAKSIPGFSSLSLSDQMSVLQSVWMEVLVLGVAQRSLPLQDELAFAEDLVLDEEGARAA GLGELGAALLQLVRRLQALRLEREEYVLLKALALANSDSVHIEDAEAVEQLREALHEALL EYEAGRAGPGGGAERRRAGRLLLTLPLLRQTAGKVLAHFYGVKLEGKVPMHKLFLEMLEA MMD Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T07VO1 | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Rimexolone | Drug Info | Approved | Arthritis | [2], [3] | |
| 2 | Pregnenolone | Drug Info | Phase 4 | Schizophrenia | [4], [5] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Dexamethasone palmitate | Drug Info | Phase 1/2 | Choroidal neovascularization | [7] | |
| Discontinued Drug(s) | [+] 6 Discontinued Drugs | + | ||||
| 1 | Rofleponide | Drug Info | Discontinued in Phase 2 | Allergic rhinitis | [8] | |
| 2 | RPR-106541 | Drug Info | Discontinued in Phase 2 | Asthma | [9] | |
| 3 | AD-121 | Drug Info | Discontinued in Phase 1/2 | Rheumatoid arthritis | [10] | |
| 4 | GW-250495 | Drug Info | Discontinued in Phase 1 | Asthma | [11] | |
| 5 | PLD-177 | Drug Info | Terminated | Allergic rhinitis | [12] | |
| 6 | Steroid hormone conjugates | Drug Info | Terminated | Cachexia | [13] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Modulator | [+] 6 Modulator drugs | + | ||||
| 1 | Rimexolone | Drug Info | [1] | |||
| 2 | Rofleponide | Drug Info | [16] | |||
| 3 | AD-121 | Drug Info | [1] | |||
| 4 | PLD-177 | Drug Info | [1] | |||
| 5 | Steroid hormone conjugates | Drug Info | [18] | |||
| 6 | NCX-1047 | Drug Info | [1] | |||
| Agonist | [+] 7 Agonist drugs | + | ||||
| 1 | Pregnenolone | Drug Info | [14] | |||
| 2 | Dexamethasone palmitate | Drug Info | [15] | |||
| 3 | RPR-106541 | Drug Info | [17] | |||
| 4 | GW-250495 | Drug Info | [1] | |||
| 5 | biochanin A | Drug Info | [20] | |||
| 6 | daidzein | Drug Info | [20] | |||
| 7 | TDT-044 | Drug Info | [1] | |||
| Inhibitor | [+] 9 Inhibitor drugs | + | ||||
| 1 | 2-(4-Hydroxy-phenyl)-4-vinyl-quinolin-6-ol | Drug Info | [19] | |||
| 2 | 4-Bromo-2-(4-hydroxy-phenyl)-quinolin-6-ol | Drug Info | [19] | |||
| 3 | 4-Chloro-2-(4-hydroxy-phenyl)-quinolin-6-ol | Drug Info | [19] | |||
| 4 | 4-Ethyl-2-(4-hydroxy-phenyl)-quinolin-6-ol | Drug Info | [19] | |||
| 5 | 4-Ethynyl-2-(4-hydroxy-phenyl)-quinolin-6-ol | Drug Info | [19] | |||
| 6 | 7-bromo-6H-chromeno[4,3-b]quinoline-3,9-diol | Drug Info | [19] | |||
| 7 | 7-ethyl-6H-chromeno[4,3-b]quinoline-3,9-diol | Drug Info | [19] | |||
| 8 | 7-ethynyl-6H-chromeno[4,3-b]quinoline-3,9-diol | Drug Info | [19] | |||
| 9 | 7-vinyl-6H-chromeno[4,3-b]quinoline-3,9-diol | Drug Info | [19] | |||
| Antagonist | [+] 2 Antagonist drugs | + | ||||
| 1 | chlordane | Drug Info | [21] | |||
| 2 | PMID17556356C1a | Drug Info | [22] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: PMID17556356C1a | Ligand Info | |||||
| Structure Description | Crystal Structure of Human Estrogen-Related Receptor alpha in Complex with a Synthetic Inverse Agonist reveals its Novel Molecular Mechanism | PDB:2PJL | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | Yes | [22] |
| PDB Sequence |
LEVLFQGPVN
291 ALVSHLLVVE301 PEKLYAMLPA320 VATLSDLFDR330 EIVVTISWAK340 SIPGFSSLSL 350 SDQMSVLQSV360 WMEVLVLGVA370 QRSLPLQDEL380 AFAEDLVLDE390 EGARAAGLGE 400 LGAALLQLVR410 RLQALRLERE420 EYVLLKALAL430 ANSDSVHIED440 AEAVEQLREA 450 LHEALLEYEA460 GRRRAGRLLL479 TLPLLRQTAG489 KVLAHFYGVK499 LEGKVPMHKL 509 FLEMLEAM
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VAL321
3.679
LEU324
3.654
SER325
4.409
LEU327
4.129
PHE328
3.803
GLU331
2.686
MET362
4.178
LEU365
4.161
VAL366
3.896
VAL369
4.011
PHE382
3.629
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| Ligand Name: 4-(4-{[(5R)-2,4-dioxo-1,3-thiazolidin-5-yl]methyl}-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile | Ligand Info | |||||
| Structure Description | Estrogen Related Receptor alpha in Complex with an Ether Based Ligand | PDB:3K6P | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [23] |
| PDB Sequence |
HHLEVLFQGP
289 VNALVSHLLV299 VEPEKLYAMP309 HLPAVATLCD326 LFDREIVVTI336 SWAKSIPGFS 346 SLSLSDQMSV356 LQSVWMEVLV366 LGVAQRSLPL376 QDELAFAEDL386 VLDEEGARAA 396 GLGELGAALL406 QLVRRLQALR416 LEREEYVLLK426 ALALANSDSV436 HIEDAEAVEQ 446 LREALHEALL456 EYEAGRGGAE470 RRAGRLLLTL481 PLLRQTAGKV491 LAHFYGVLEG 502 KVPMHKLFLE512 MLEAMM
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VAL321
4.145
LEU324
3.253
CYS325
2.333
LEU327
3.802
PHE328
3.158
GLU331
3.324
MET362
4.413
LEU365
3.824
VAL366
4.292
VAL369
3.662
ARG372
3.225
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 2.02E-04 |
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| Closeness centrality | 2.03E-01 | Radiality | 1.35E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 2.65E+01 | Topological coefficient | 5.00E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | PPARA activates gene expression | |||||
| 2 | Transcriptional activation of mitochondrial biogenesis | |||||
| 3 | Nuclear Receptor transcription pathway | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | Mitochondrial Gene Expression | |||||
| 2 | Regulation of Lipid Metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha) | |||||
| 3 | Nuclear Receptors | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 622). | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7099). | |||||
| REF 3 | ClinicalTrials.gov (NCT00471419) Phase II Study of AL-2178 (FID 109980) in the Treatment of Dry Eye. U.S. National Institutes of Health. | |||||
| REF 4 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2376). | |||||
| REF 5 | ClinicalTrials.gov (NCT01409096) Study Using Pregnenolone to Treat Bipolar Depression. U.S. National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT02270450) S1316, Surgery or Non-Surgical Management in Treating Patients With Intra-Abdominal Cancer and Bowel Obstruction. U.S. National Institutes of Health. | |||||
| REF 7 | Clinical pipeline report, company report or official report of Santen Pharmaceutical. | |||||
| REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007303) | |||||
| REF 9 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007341) | |||||
| REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015041) | |||||
| REF 11 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010129) | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020887) | |||||
| REF 13 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015954) | |||||
| REF 14 | Suppression of adrenal function by low-dose prednisone: assessment with 24-hour urinary steroid hormone profiles--a review of five cases. Altern Med Rev. 2006 Mar;11(1):40-6. | |||||
| REF 15 | Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet. 2002 Jul 20;360(9328):211-8. | |||||
| REF 16 | Direct activation of GABAA receptors by loreclezole, an anticonvulsant drug with selectivity for the beta-subunit. Neuropharmacology. 1996;35(12):1753-60. | |||||
| REF 17 | Use of the steroid derivative RPR 106541 in combination with site-directed mutagenesis for enhanced cytochrome P-450 3A4 structure/function analysis. J Pharmacol Exp Ther. 1999 Aug;290(2):594-602. | |||||
| REF 18 | The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol (Oxf). 1998 Oct;49(4):421-32. | |||||
| REF 19 | ERbeta ligands. Part 6: 6H-Chromeno[4,3-b]quinolines as a new series of estrogen receptor beta-selective ligands. Bioorg Med Chem Lett. 2007 Jul 15;17(14):4053-6. | |||||
| REF 20 | Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors. Mol Cancer Res. 2003 Nov;1(13):981-91. | |||||
| REF 21 | Two organochlorine pesticides, toxaphene and chlordane, are antagonists for estrogen-related receptor alpha-1 orphan receptor. Cancer Res. 1999 Sep 15;59(18):4519-24. | |||||
| REF 22 | Crystal structure of human estrogen-related receptor alpha in complex with a synthetic inverse agonist reveals its novel molecular mechanism. J Biol Chem. 2007 Aug 10;282(32):23231-9. | |||||
| REF 23 | Development of Diaryl Ether based ligands for Estrogen Related Receptor alpha as Potential Anti-Diabetic Agents. | |||||
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