Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC8P9GN)

• DOT Name: Nuclear receptor subfamily 0 group B member 1 (NR0B1)
• Synonyms: DSS-AHC critical region on the X chromosome protein 1; Nuclear receptor DAX-1
• Gene Name: NR0B1
• Related Disease:
  X-linked adrenal hypoplasia congenita
  46,XY sex reversal 2
• UniProt ID: NR0B1_HUMAN
• PDB ID: 4RWV
• Pfam ID: PF00104 ; PF14046
• Sequence:
  MAGENHQWQGSILYNMLMSAKQTRAAPEAPETRLVDQCWGCSCGDEPGVGREGLLGGRNV
  ALLYRCCFCGKDHPRQGSILYSMLTSAKQTYAAPKAPEATLGPCWGCSCGSDPGVGRAGL
  PGGRPVALLYRCCFCGEDHPRQGSILYSLLTSSKQTHVAPAAPEARPGGAWWDRSYFAQR
  PGGKEALPGGRATALLYRCCFCGEDHPQQGSTLYCVPTSTNQAQAAPEERPRAPWWDTSS
  GALRPVALKSPQVVCEAASAGLLKTLRFVKYLPCFQVLPLDQQLVLVRNCWASLLMLELA
  QDRLQFETVEVSEPSMLQKILTTRRRETGGNEPLPVPTLQHHLAPPAEARKVPSASQVQA
  IKCFLSKCWSLNISTKEYAYLKGTVLFNPDVPGLQCVKYIQGLQWGTQQILSEHTRMTHQ
  GPHDRFIELNSTLFLLRFINANVIAELFFRPIIGTVSMDDMMLEMLCTKI
• Function: Orphan nuclear receptor. Component of a cascade required for the development of the hypothalamic-pituitary-adrenal-gonadal axis. Acts as a coregulatory protein that inhibits the transcriptional activity of other nuclear receptors through heterodimeric interactions. May also have a role in the development of the embryo and in the maintenance of embryonic stem cell pluripotency.
• KEGG Pathway: Cortisol synthesis and secretion (hsa04927)
• Reactome Pathway: Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked adrenal hypoplasia congenita	DISNMXY8	Definitive	X-linked	[1]
46,XY sex reversal 2	DIS0USUN	Moderate	X-linked	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Nuclear receptor subfamily 0 group B member 1 (NR0B1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Nuclear receptor subfamily 0 group B member 1 (NR0B1).	[11]

10 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 subfamily 0 group B member 1 (NR0B1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nuclear receptor subfamily 0 group B member 1 (NR0B1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nuclear receptor subfamily 0 group B member 1 (NR0B1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nuclear receptor subfamily 0 group B member 1 (NR0B1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nuclear receptor subfamily 0 group B member 1 (NR0B1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Nuclear receptor subfamily 0 group B member 1 (NR0B1).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Nuclear receptor subfamily 0 group B member 1 (NR0B1).	[8]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Nuclear receptor subfamily 0 group B member 1 (NR0B1).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nuclear receptor subfamily 0 group B member 1 (NR0B1).	[12]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Nuclear receptor subfamily 0 group B member 1 (NR0B1).	[13]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] 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.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Upregulation of genes orchestrating keratinocyte differentiation, including the novel marker gene ID2, by contact sensitizers in human bulge-derived keratinocytes. J Biochem Mol Toxicol. 2010 Jan-Feb;24(1):10-20.
• [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] Targeting the epigenetic readers in Ewing sarcoma inhibits the oncogenic transcription factor EWS/Fli1. Oncotarget. 2016 Apr 26;7(17):24125-40. doi: 10.18632/oncotarget.8214.
• [13] The effect of valproate and levetiracetam on steroidogenesis in forskolin-stimulated H295R cells. Epilepsia. 2010 Nov;51(11):2280-8.