Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTDTUSP)

• DOT Name: Steroid hormone receptor ERR1 (ESRRA)
• Synonyms: Estrogen receptor-like 1; Estrogen-related receptor alpha; ERR-alpha; Nuclear receptor subfamily 3 group B member 1
• Gene Name: ESRRA
• UniProt ID: ERR1_HUMAN
• PDB ID: 1XB7; 2PJL; 3D24; 3K6P; 7E2E
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MSSQVVGIEPLYIKAEPASPDSPKGSSETETEPPVALAPGPAPTRCLPGHKEEEDGEGAG
  PGEQGGGKLVLSSLPKRLCLVCGDVASGYHYGVASCEACKAFFKRTIQGSIEYSCPASNE
  CEITKRRRKACQACRFTKCLRVGMLKEGVRLDRVRGGRQKYKRRPEVDPLPFPGPFPAGP
  LAVAGGPRKTAAPVNALVSHLLVVEPEKLYAMPDPAGPDGHLPAVATLCDLFDREIVVTI
  SWAKSIPGFSSLSLSDQMSVLQSVWMEVLVLGVAQRSLPLQDELAFAEDLVLDEEGARAA
  GLGELGAALLQLVRRLQALRLEREEYVLLKALALANSDSVHIEDAEAVEQLREALHEALL
  EYEAGRAGPGGGAERRRAGRLLLTLPLLRQTAGKVLAHFYGVKLEGKVPMHKLFLEMLEA
  MMD
• Function: Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Induces the expression of PERM1 in the skeletal muscle.
• Reactome Pathway:
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Nuclear Receptor transcription pathway (R-HSA-383280)
  Regulation of RUNX2 expression and activity (R-HSA-8939902)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

20 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[1]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Steroid hormone receptor ERR1 (ESRRA).	[2]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Steroid hormone receptor ERR1 (ESRRA).	[3]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[2]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[4]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Steroid hormone receptor ERR1 (ESRRA).	[5]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[6]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[7]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[8]
Dinoprostone	DMTYOPD	Approved	Dinoprostone increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[12]
Rocilinostat	DMSTH01	Phase 2	Rocilinostat decreases the expression of Steroid hormone receptor ERR1 (ESRRA).	[14]
G1	DMTV42K	Phase 1/2	G1 increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[4]
BUTAPROST	DMVYNJZ	Patented	BUTAPROST increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[9]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the activity of Steroid hormone receptor ERR1 (ESRRA).	[19]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Steroid hormone receptor ERR1 (ESRRA).	[9]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the expression of Steroid hormone receptor ERR1 (ESRRA).	[14]

4 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the binding of Steroid hormone receptor ERR1 (ESRRA).	[10]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene affects the binding of Steroid hormone receptor ERR1 (ESRRA).	[13]
biochanin A	DM0HPWY	Investigative	biochanin A affects the binding of Steroid hormone receptor ERR1 (ESRRA).	[10]
Flavone	DMEQH6J	Investigative	Flavone affects the binding of Steroid hormone receptor ERR1 (ESRRA).	[10]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Steroid hormone receptor ERR1 (ESRRA).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Steroid hormone receptor ERR1 (ESRRA).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Steroid hormone receptor ERR1 (ESRRA).	[17]

References

• [1] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [2] [Regulation of orphan receptor ERR alpha by estrogen and progesterone in endometrial carcinoma cell line]. Beijing Da Xue Xue Bao Yi Xue Ban. 2005 Jun 18;37(3):281-3.
• [3] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [4] Regulation of ERRalpha gene expression by estrogen receptor agonists and antagonists in SKBR3 breast cancer cells: differential molecular mechanisms mediated by g protein-coupled receptor GPR30/GPER-1. Mol Endocrinol. 2010 May;24(5):969-80. doi: 10.1210/me.2009-0148. Epub 2010 Mar 8.
• [5] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [6] Troglitazone induces cytotoxicity in part by promoting the degradation of peroxisome proliferator-activated receptor co-activator-1 protein. Br J Pharmacol. 2010 Oct;161(4):771-81. doi: 10.1111/j.1476-5381.2010.00900.x.
• [7] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [8] Plasmatic concentration of organochlorine lindane acts as metabolic disruptors in HepG2 liver cell line by inducing mitochondrial disorder. Toxicol Appl Pharmacol. 2013 Oct 15;272(2):325-34.
• [9] Estrogen receptor-related receptor alpha mediates up-regulation of aromatase expression by prostaglandin E2 in prostate stromal cells. Mol Endocrinol. 2010 Jun;24(6):1175-86.
• [10] Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors. Mol Cancer Res. 2003 Nov;1(13):981-91.
• [11] Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling. Hum Mol Genet. 2014 Apr 15;23(8):2106-19.
• [12] Genistein affects the expression of genes involved in blood pressure regulation and angiogenesis in primary human endothelial cells. Nutr Metab Cardiovasc Dis. 2006 Jan;16(1):35-43. doi: 10.1016/j.numecd.2005.03.003. Epub 2005 Jul 28.
• [13] 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8880-4. doi: 10.1073/pnas.151244398. Epub 2001 Jul 10.
• [14] ERR contributes to HDAC6-induced chemoresistance of osteosarcoma cells. Cell Biol Toxicol. 2023 Jun;39(3):813-825. doi: 10.1007/s10565-021-09651-8. Epub 2021 Sep 15.
• [15] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [16] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Bisphenol A exposure is associated with in vivo estrogenic gene expression in adults. Environ Health Perspect. 2011 Dec;119(12):1788-93. doi: 10.1289/ehp.1103809. Epub 2011 Aug 10.
• [19] Differential regulation of the orphan nuclear receptor small heterodimer partner (SHP) gene promoter by orphan nuclear receptor ERR isoforms. J Biol Chem. 2002 Jan 18;277(3):1739-48. doi: 10.1074/jbc.M106140200. Epub 2001 Nov 8.