Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9CVF41)

• DOT Name: Nuclear receptor subfamily 1 group D member 2 (NR1D2)
• Synonyms: Orphan nuclear hormone receptor BD73; Rev-erb alpha-related receptor; RVR; Rev-erb-beta; V-erbA-related protein 1-related; EAR-1R
• Gene Name: NR1D2
• Related Disease:
  Anemia
  Astrocytoma
  Breast cancer
  Breast carcinoma
  Cryohydrocytosis
  Endometriosis
  Hepatitis C virus infection
  Liver cirrhosis
  Lung cancer
  Lung carcinoma
  Ulcerative colitis
  Advanced cancer
  Kidney cancer
  Renal carcinoma
  Adult glioblastoma
  Glioblastoma multiforme
• UniProt ID: NR1D2_HUMAN
• PDB ID: 2V0V; 2V7C; 3CQV; 4N73; 6WMQ; 6WMS
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MEVNAGGVIAYISSSSSASSPASCHSEGSENSFQSSSSSVPSSPNSSNSDTNGNPKNGDL
  ANIEGILKNDRIDCSMKTSKSSAPGMTKSHSGVTKFSGMVLLCKVCGDVASGFHYGVHAC
  EGCKGFFRRSIQQNIQYKKCLKNENCSIMRMNRNRCQQCRFKKCLSVGMSRDAVRFGRIP
  KREKQRMLIEMQSAMKTMMNSQFSGHLQNDTLVEHHEQTALPAQEQLRPKPQLEQENIKS
  SSPPSSDFAKEEVIGMVTRAHKDTFMYNQEQQENSAESMQPQRGERIPKNMEQYNLNHDH
  CGNGLSSHFPCSESQQHLNGQFKGRNIMHYPNGHAICIANGHCMNFSNAYTQRVCDRVPI
  DGFSQNENKNSYLCNTGGRMHLVCPMSKSPYVDPHKSGHEIWEEFSMSFTPAVKEVVEFA
  KRIPGFRDLSQHDQVNLLKAGTFEVLMVRFASLFDAKERTVTFLSGKKYSVDDLHSMGAG
  DLLNSMFEFSEKLNALQLSDEEMSLFTAVVLVSADRSGIENVNSVEALQETLIRALRTLI
  MKNHPNEASIFTKLLLKLPDLRSLNNMHSEELLAFKVHP
• Function: Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components BMAL1 and CLOCK. Also regulates genes involved in metabolic functions, including lipid metabolism and the inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nuclegotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and also negatively regulates the expression of NR1D1. Regulates lipid and energy homeostasis in the skeletal muscle via repression of genes involved in lipid metabolism and myogenesis including: CD36, FABP3, FABP4, UCP3, SCD1 and MSTN. Regulates hepatic lipid metabolism via the repression of APOC3. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). In addition to its activity as a repressor, can also act as a transcriptional activator. Acts as a transcriptional activator of the sterol regulatory element-binding protein 1 (SREBF1) and the inflammatory mediator interleukin-6 (IL6) in the skeletal muscle. Plays a role in the regulation of circadian sleep/wake cycle; essential for maintaining wakefulness during the dark phase or active period. Key regulator of skeletal muscle mitochondrial function; negatively regulates the skeletal muscle expression of core clock genes and genes involved in mitochondrial biogenesis, fatty acid beta-oxidation and lipid metabolism. May play a role in the circadian control of neutrophilic inflammation in the lung.
• Tissue Specificity: Widely expressed. Expressed at high levels in the liver, adipose tissue, skeletal muscle and brain. Expression oscillates diurnally in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as in peripheral tissues.
• KEGG Pathway: Circadian rhythm (hsa04710)
• Reactome Pathway: Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anemia	DISTVL0C	Strong	Biomarker	[1]
Astrocytoma	DISL3V18	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cryohydrocytosis	DISMQHL3	Strong	Genetic Variation	[4]
Endometriosis	DISX1AG8	Strong	Biomarker	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[6]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[8]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[9]
Kidney cancer	DISBIPKM	moderate	Biomarker	[10]
Renal carcinoma	DISER9XT	moderate	Biomarker	[10]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[11]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[11]

23 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 1 group D member 2 (NR1D2).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[18]
Marinol	DM70IK5	Approved	Marinol increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[19]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[20]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[21]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[22]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[22]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[23]
Chenodiol	DMQ8JIK	Approved	Chenodiol affects the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[30]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[31]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[32]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Nuclear receptor subfamily 1 group D member 2 (NR1D2).	[33]

References

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