Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPBE9R1)

• DOT Name: Nuclear receptor subfamily 4 group A member 3 (NR4A3)
• Synonyms: Mitogen-induced nuclear orphan receptor; Neuron-derived orphan receptor 1; Nuclear hormone receptor NOR-1
• Gene Name: NR4A3
• UniProt ID: NR4A3_HUMAN
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MPCVQAQYSPSPPGSSYAAQTYSSEYTTEIMNPDYTKLTMDLGSTEITATATTSLPSIST
  FVEGYSSNYELKPSCVYQMQRPLIKVEEGRAPSYHHHHHHHHHHHHHHQQQHQQPSIPPA
  SSPEDEVLPSTSMYFKQSPPSTPTTPAFPPQAGALWDEALPSAPGCIAPGPLLDPPMKAV
  PTVAGARFPLFHFKPSPPHPPAPSPAGGHHLGYDPTAAAALSLPLGAAAAAGSQAAALES
  HPYGLPLAKRAAPLAFPPLGLTPSPTASSLLGESPSLPSPPSRSSSSGEGTCAVCGDNAA
  CQHYGVRTCEGCKGFFKRTVQKNAKYVCLANKNCPVDKRRRNRCQYCRFQKCLSVGMVKE
  VVRTDSLKGRRGRLPSKPKSPLQQEPSQPSPPSPPICMMNALVRALTDSTPRDLDYSRYC
  PTDQAAAGTDAEHVQQFYNLLTASIDVSRSWAEKIPGFTDLPKEDQTLLIESAFLELFVL
  RLSIRSNTAEDKFVFCNGLVLHRLQCLRGFGEWLDSIKDFSLNLQSLNLDIQALACLSAL
  SMITERHGLKEPKRVEELCNKITSSLKDHQSKGQALEPTESKVLGALVELRKICTLGLQR
  IFYLKLEDLVSPPSIIDKLFLDTLPF
• Function: Transcriptional activator that binds to regulatory elements in promoter regions in a cell- and response element (target)-specific manner. Induces gene expression by binding as monomers to the NR4A1 response element (NBRE) 5'-AAAAGGTCA-3' site and as homodimers to the Nur response element (NurRE) site in the promoter of their regulated target genes. Plays a role in the regulation of proliferation, survival and differentiation of many different cell types and also in metabolism and inflammation. Mediates proliferation of vascular smooth muscle, myeloid progenitor cell and type B pancreatic cells; promotes mitogen-induced vascular smooth muscle cell proliferation through transactivation of SKP2 promoter by binding a NBRE site. Upon PDGF stimulation, stimulates vascular smooth muscle cell proliferation by regulating CCND1 and CCND2 expression. In islets, induces type B pancreatic cell proliferation through up-regulation of genes that activate cell cycle, as well as genes that cause degradation of the CDKN1A. Negatively regulates myeloid progenitor cell proliferation by repressing RUNX1 in a NBRE site-independent manner. During inner ear, plays a role as a key mediator of the proliferative growth phase of semicircular canal development. Mediates also survival of neuron and smooth muscle cells; mediates CREB-induced neuronal survival, and during hippocampus development, plays a critical role in pyramidal cell survival and axonal guidance. Is required for S phase entry of the cell cycle and survival of smooth muscle cells by inducing CCND1, resulting in RB1 phosphorylation. Binds to NBRE motif in CCND1 promoter, resulting in the activation of the promoter and CCND1 transcription. Also plays a role in inflammation; upon TNF stimulation, mediates monocyte adhesion by inducing the expression of VCAM1 and ICAM1 by binding to the NBRE consensus site. In mast cells activated by Fc-epsilon receptor cross-linking, promotes the synthesis and release of cytokines but impairs events leading to degranulation. Also plays a role in metabolism; by modulating feeding behavior; and by playing a role in energy balance by inhibiting the glucocorticoid-induced orexigenic neuropeptides AGRP expression, at least in part by forming a complex with activated NR3C1 on the AGRP- glucocorticoid response element (GRE), and thus weakening the DNA binding activity of NR3C1. Upon catecholamines stimulation, regulates gene expression that controls oxidative metabolism in skeletal muscle. Plays a role in glucose transport by regulating translocation of the SLC2A4 glucose transporter to the cell surface. Finally, during gastrulation plays a crucial role in the formation of anterior mesoderm by controlling cell migration. Inhibits adipogenesis. Also participates in cardiac hypertrophy by activating PARP1.
• Tissue Specificity: Isoform alpha is highly expressed in skeletal muscle. Isoform beta is highly expressed in skeletal muscle and low expressed in fetal brain and placenta.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mercaptopurine	DMTM2IK	Approved	Nuclear receptor subfamily 4 group A member 3 (NR4A3) increases the Soft tissue neoplasms malignant and unspecified ADR of Mercaptopurine.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[7]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[8]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[7]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[9]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[7]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[10]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[11]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[12]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[7]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[7]
Ximelegatran	DMU8ANS	Approved	Ximelegatran decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[14]
Cethrin	DMD3XMW	Phase 1/2	Cethrin decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[16]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[17]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[20]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[21]
eucalyptol	DME5CK3	Investigative	eucalyptol decreases the expression of Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[22]

1 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 Nuclear receptor subfamily 4 group A member 3 (NR4A3).	[15]

References

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• [13] Simvastatin inhibits NOR-1 expression induced by hyperlipemia by interfering with CREB activation. Cardiovasc Res. 2005 Aug 1;67(2):333-41. doi: 10.1016/j.cardiores.2005.03.016. Epub 2005 Apr 21.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology. 2009 May;150(5):2211-9.
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• [19] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [20] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [21] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [22] Transcriptome Analysis Reveals the Anti-Tumor Mechanism of Eucalyptol Treatment on Neuroblastoma Cell Line SH-SY5Y. Neurochem Res. 2022 Dec;47(12):3854-3862. doi: 10.1007/s11064-022-03786-8. Epub 2022 Nov 4.
• [23] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.