Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTPNQAC)

• DTT Name: Estrogen-related receptor-alpha (ESRRA)
• 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
• Gene Name: ESRRA
• DTT Type: Successful target; [1]
• BioChemical Class: Nuclear hormone receptor
• UniProt ID: ERR1_HUMAN
• TTD ID: T72841
• Sequence:
  MSSQVVGIEPLYIKAEPASPDSPKGSSETETEPPVALAPGPAPTRCLPGHKEEEDGEGAG
  PGEQGGGKLVLSSLPKRLCLVCGDVASGYHYGVASCEACKAFFKRTIQGSIEYSCPASNE
  CEITKRRRKACQACRFTKCLRVGMLKEGVRLDRVRGGRQKYKRRPEVDPLPFPGPFPAGP
  LAVAGGPRKTAAPVNALVSHLLVVEPEKLYAMPDPAGPDGHLPAVATLCDLFDREIVVTI
  SWAKSIPGFSSLSLSDQMSVLQSVWMEVLVLGVAQRSLPLQDELAFAEDLVLDEEGARAA
  GLGELGAALLQLVRRLQALRLEREEYVLLKALALANSDSVHIEDAEAVEQLREALHEALL
  EYEAGRAGPGGGAERRRAGRLLLTLPLLRQTAGKVLAHFYGVKLEGKVPMHKLFLEMLEA
  MMD
• 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'.
• Reactome Pathway:
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Nuclear Receptor transcription pathway (R-HSA-383280)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Rimexolone	DMTAREC	Arthritis	FA20	Approved	[1]
Pregnenolone	DM6VFO1	Schizophrenia	6A20	Phase 4	[2]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
D-5519	DM9FAJM	Asthma	CA23	Phase 3	[3]
Dexamethasone palmitate	DMCMT4V	Choroidal neovascularization	9B76	Phase 1/2	[4]

6 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Rofleponide	DM6OSPQ	Allergic rhinitis	CA08.0	Discontinued in Phase 2	[5]
RPR-106541	DMRGC5B	Asthma	CA23	Discontinued in Phase 2	[6]
AD-121	DMB8XJM	Rheumatoid arthritis	FA20	Discontinued in Phase 1/2	[1]
GW-250495	DMWJZAP	Asthma	CA23	Discontinued in Phase 1	[1]
PLD-177	DMPHUBO	Allergic rhinitis	CA08.0	Terminated	[1]
Steroid hormone conjugates	DMOJM08	Cachexia	MG20	Terminated	[7]

18 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(4-Hydroxy-phenyl)-4-vinyl-quinolin-6-ol	DM81G2U	Discovery agent	N.A.	Investigative	[8]
4-Bromo-2-(4-hydroxy-phenyl)-quinolin-6-ol	DMPSRAC	Discovery agent	N.A.	Investigative	[8]
4-Chloro-2-(4-hydroxy-phenyl)-quinolin-6-ol	DMKJ18X	Discovery agent	N.A.	Investigative	[8]
4-Ethyl-2-(4-hydroxy-phenyl)-quinolin-6-ol	DMTIY89	Discovery agent	N.A.	Investigative	[8]
4-Ethynyl-2-(4-hydroxy-phenyl)-quinolin-6-ol	DMXLZAT	Discovery agent	N.A.	Investigative	[8]
7-bromo-6H-chromeno[4,3-b]quinoline-3,9-diol	DMX85IF	Discovery agent	N.A.	Investigative	[8]
7-chloro-6H-chromeno[4,3-b]quinoline-3,9-diol	DMRNZYQ	Discovery agent	N.A.	Investigative	[8]
7-ethyl-6H-chromeno[4,3-b]quinoline-3,9-diol	DMSFODU	Discovery agent	N.A.	Investigative	[8]
7-ethynyl-6H-chromeno[4,3-b]quinoline-3,9-diol	DMJWCAH	Discovery agent	N.A.	Investigative	[8]
7-vinyl-6H-chromeno[4,3-b]quinoline-3,9-diol	DM14OHR	Discovery agent	N.A.	Investigative	[8]
biochanin A	DM0HPWY	Discovery agent	N.A.	Investigative	[9]
chlordane	DMMHU8G	Discovery agent	N.A.	Investigative	[10]
daidzein	DMRFTJX	Discovery agent	N.A.	Investigative	[9]
NCX-1047	DM1FOSP	Dermatitis	EA80-EA89	Investigative	[1]
PMID17556356C1a	DM7Z2WV	Discovery agent	N.A.	Investigative	[11]
TDT-044	DMRU8WT	Dermatological disease	DA24.Y	Investigative	[1]
toxaphene	DM4R657	Discovery agent	N.A.	Investigative	[10]
XCT790	DMZ7N8D	Discovery agent	N.A.	Investigative	[12]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Asthma	CA23	Nasal and bronchial airway	2.85E-08	0.26	0.47
Schizophrenia	6A20	Pre-frontal cortex	9.34E-01	1.47E-02	0.06
Schizophrenia	6A20	Superior temporal cortex	2.09E-01	-0.07	-0.62
Rheumatoid arthritis	FA20	Synovial tissue	3.46E-01	0.06	0.14
Atopic dermatitis	EA90	Skin	6.95E-14	0.51	3.32

References

• [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).
• [2] 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.
• [3] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007199)
• [4] Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet. 2002 Jul 20;360(9328):211-8.
• [5] Direct activation of GABAA receptors by loreclezole, an anticonvulsant drug with selectivity for the beta-subunit. Neuropharmacology. 1996;35(12):1753-60.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors. Mol Cancer Res. 2003 Nov;1(13):981-91.
• [10] 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.
• [11] 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.
• [12] Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8912-7.