Details of Drug Off-Target (DOT)

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

• DOT Name: Nuclear receptor-binding factor 2 (NRBF2)
• Synonyms: NRBF-2; Comodulator of PPAR and RXR
• Gene Name: NRBF2
• Related Disease:
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Juvenile idiopathic arthritis
• UniProt ID: NRBF2_HUMAN
• PDB ID: 4ZEY
• Pfam ID: PF08961 ; PF17169
• Sequence:
  MEVMEGPLNLAHQQSRRADRLLAAGKYEEAISCHKKAAAYLSEAMKLTQSEQAHLSLELQ
  RDSHMKQLLLIQERWKRAQREERLKAQQNTDKDAAAHLQTSHKPSAEDAEGQSPLSQKYS
  PSTEKCLPEIQGIFDRDPDTLLYLLQQKSEPAEPCIGSKAPKDDKTIIEEQATKIADLKR
  HVEFLVAENERLRKENKQLKAEKARLLKGPIEKELDVDADFVETSELWSLPPHAETATAS
  STWQKFAANTGKAKDIPIPNLPPLDFPSPELPLMELSEDILKGFMNN
• Function: May modulate transcriptional activation by target nuclear receptors. Can act as transcriptional activator (in vitro); Involved in starvation-induced autophagy probably by its association with PI3K complex I (PI3KC3-C1). However, effects has been described variably. Involved in the induction of starvation-induced autophagy. Stabilzes PI3KC3-C1 assembly and enhances ATG14-linked lipid kinase activity of PIK3C3. Proposed to negatively regulate basal and starvation-induced autophagy and to inhibit PIK3C3 activity by modulating interactions in PI3KC3-C1. May be involved in autophagosome biogenesis. May play a role in neural progenitor cell survival during differentiation.
• Tissue Specificity: Detected in keratinocytes, liver and placenta . Expressed in a subset of cells in pediatric medulloblastoma .
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway: Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Genetic Variation	[3]

4 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 Nuclear receptor-binding factor 2 (NRBF2).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Nuclear receptor-binding factor 2 (NRBF2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Nuclear receptor-binding factor 2 (NRBF2).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nuclear receptor-binding factor 2 (NRBF2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nuclear receptor-binding factor 2 (NRBF2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nuclear receptor-binding factor 2 (NRBF2).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Nuclear receptor-binding factor 2 (NRBF2).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Nuclear receptor-binding factor 2 (NRBF2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nuclear receptor-binding factor 2 (NRBF2).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Nuclear receptor-binding factor 2 (NRBF2).	[13]

References

• [1] Autophagy protein NRBF2 has reduced expression in Alzheimer's brains and modulates memory and amyloid-beta homeostasis in mice.Mol Neurodegener. 2019 Nov 27;14(1):43. doi: 10.1186/s13024-019-0342-4.
• [2] Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression.Am J Hum Genet. 2015 Jul 2;97(1):22-34. doi: 10.1016/j.ajhg.2015.05.002. Epub 2015 Jun 11.
• [3] Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13.Arthritis Rheum. 2012 Aug;64(8):2781-91. doi: 10.1002/art.34429.
• [4] Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes. Chem Res Toxicol. 2017 Oct 16;30(10):1847-1854. doi: 10.1021/acs.chemrestox.7b00171. Epub 2017 Sep 13.
• [5] 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.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.