Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC3A0KU)

• DOT Name: Estrogen-related receptor gamma (ESRRG)
• Synonyms: ERR gamma-2; Estrogen receptor-related protein 3; Nuclear receptor subfamily 3 group B member 3
• Gene Name: ESRRG
• UniProt ID: ERR3_HUMAN
• PDB ID: 1KV6 ; 1TFC ; 1VJB ; 2E2R ; 2EWP ; 2GP7 ; 2GPO ; 2GPP ; 2GPU ; 2GPV ; 2P7A ; 2P7G ; 2P7Z ; 2ZAS ; 2ZBS ; 2ZKC ; 5YSO ; 6A6K ; 6I61 ; 6I62 ; 6I63 ; 6I64 ; 6I65 ; 6I66 ; 6I67 ; 6K3N ; 6KNR ; 6XXC ; 6XY5 ; 6Y18 ; 6Y1D ; 6Y3W ; 6Y58 ; 8B4Q ; 8BJG ; 8BJN ; 8BM5 ; 8IFO
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MDSVELCLPESFSLHYEEELLCRMSNKDRHIDSSCSSFIKTEPSSPASLTDSVNHHSPGG
  SSDASGSYSSTMNGHQNGLDSPPLYPSAPILGGSGPVRKLYDDCSSTIVEDPQTKCEYML
  NSMPKRLCLVCGDIASGYHYGVASCEACKAFFKRTIQGNIEYSCPATNECEITKRRRKSC
  QACRFMKCLKVGMLKEGVRLDRVRGGRQKYKRRIDAENSPYLNPQLVQPAKKPYNKIVSH
  LLVAEPEKIYAMPDPTVPDSDIKALTTLCDLADRELVVIIGWAKHIPGFSTLSLADQMSL
  LQSAWMEILILGVVYRSLSFEDELVYADDYIMDEDQSKLAGLLDLNNAILQLVKKYKSMK
  LEKEEFVTLKAIALANSDSMHIEDVEAVQKLQDVLHEALQDYEAGQHMEDPRRAGKMLMT
  LPLLRQTSTKAVQHFYNIKLEGKVPMHKLFLEMLEAKV
• Function: Orphan receptor that acts as a transcription activator in the absence of bound ligand. Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements. Induces the expression of PERM1 in the skeletal muscle.
• Tissue Specificity: Expressed in the heart, kidney, brain, lung, bone marrow, adrenal gland, trachea, spinal cord and thyroid gland.
• Reactome Pathway: Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
2-arachidonoylglycerol	DMM0KOJ	Investigative	Estrogen-related receptor gamma (ESRRG) increases the abundance of 2-arachidonoylglycerol.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Estrogen-related receptor gamma (ESRRG).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Estrogen-related receptor gamma (ESRRG).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Estrogen-related receptor gamma (ESRRG).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Estrogen-related receptor gamma (ESRRG).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Estrogen-related receptor gamma (ESRRG).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Estrogen-related receptor gamma (ESRRG).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Estrogen-related receptor gamma (ESRRG).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Estrogen-related receptor gamma (ESRRG).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Estrogen-related receptor gamma (ESRRG).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Estrogen-related receptor gamma (ESRRG).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Estrogen-related receptor gamma (ESRRG).	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of Estrogen-related receptor gamma (ESRRG).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Estrogen-related receptor gamma (ESRRG).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Estrogen-related receptor gamma (ESRRG).	[15]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Estrogen-related receptor gamma (ESRRG).	[16]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the activity of Estrogen-related receptor gamma (ESRRG).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Estrogen-related receptor gamma (ESRRG).	[2]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Estrogen-related receptor gamma (ESRRG).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Estrogen-related receptor gamma (ESRRG).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Estrogen-related receptor gamma (ESRRG).	[20]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Estrogen-related receptor gamma (ESRRG).	[21]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Estrogen-related receptor gamma (ESRRG).	[22]
Tetramethylbutylphenol	DMW9CH2	Investigative	Tetramethylbutylphenol increases the activity of Estrogen-related receptor gamma (ESRRG).	[23]
Fenthion	DMKEG49	Investigative	Fenthion increases the activity of Estrogen-related receptor gamma (ESRRG).	[24]
ACEA	DMWX3HT	Investigative	ACEA increases the expression of Estrogen-related receptor gamma (ESRRG).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol affects the binding of Estrogen-related receptor gamma (ESRRG).	[14]
HPTE	DMRPZD4	Investigative	HPTE affects the binding of Estrogen-related receptor gamma (ESRRG).	[25]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Bisphenol A effects on gene expression in adipocytes from children: association with metabolic disorders. J Mol Endocrinol. 2015 Jun;54(3):289-303.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] 9-Tetrahydrocannabinol leads to endoplasmic reticulum stress and mitochondrial dysfunction in human BeWo trophoblasts. Reprod Toxicol. 2019 Aug;87:21-31. doi: 10.1016/j.reprotox.2019.04.008. Epub 2019 May 1.
• [13] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [14] 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.
• [15] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [16] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [17] Requirements for transcriptional regulation by the orphan nuclear receptor ERRgamma. Mol Cell Endocrinol. 2004 Apr 30;219(1-2):151-60. doi: 10.1016/j.mce.2004.01.002.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Gene expression is altered after bisphenol A exposure in human fetal oocytes in vitro. Mol Hum Reprod. 2012 Apr;18(4):171-83. doi: 10.1093/molehr/gar074. Epub 2011 Nov 25.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [22] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [23] Insights into the activation mechanism of human estrogen-related receptor by environmental endocrine disruptors. Cell Mol Life Sci. 2019 Dec;76(23):4769-4781. doi: 10.1007/s00018-019-03129-x. Epub 2019 May 24.
• [24] Impact of environmental chemicals on key transcription regulators and correlation to toxicity end points within EPA's ToxCast program. Chem Res Toxicol. 2010 Mar 15;23(3):578-90. doi: 10.1021/tx900325g.
• [25] Structure-based Identification of Endocrine Disrupting Pesticides Targeting Breast Cancer Proteins. Toxicology. 2020 Jun;439:152459. doi: 10.1016/j.tox.2020.152459. Epub 2020 Apr 9.
• [26] An inverse agonist of estrogen-related receptor regulates 2-arachidonoylglycerol synthesis by modulating diacylglycerol lipase expression in alcohol-intoxicated mice. Arch Toxicol. 2020 Feb;94(2):427-438. doi: 10.1007/s00204-019-02648-7. Epub 2020 Jan 7.