Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRWEJ65)

• DOT Name: Nuclear receptor-binding protein (NRBP1)
• Gene Name: NRBP1
• Related Disease:
  Type-1/2 diabetes
  Colorectal carcinoma
  Gout
  Myeloid leukaemia
  Neoplasm
  Oral cancer
  Oral cavity carcinoma
  Benign prostatic hyperplasia
  Prostate cancer
  Prostate carcinoma
  Bladder cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: NRBP_HUMAN
• Pfam ID: PF00069
• Sequence:
  MSEGESQTVLSSGSDPKVESSSSAPGLTSVSPPVTSTTSAASPEEEEESEDESEILEESP
  CGRWQKRREEVNQRNVPGIDSAYLAMDTEEGVEVVWNEVQFSERKNYKLQEEKVRAVFDN
  LIQLEHLNIVKFHKYWADIKENKARVIFITEYMSSGSLKQFLKKTKKNHKTMNEKAWKRW
  CTQILSALSYLHSCDPPIIHGNLTCDTIFIQHNGLIKIGSVAPDTINNHVKTCREEQKNL
  HFFAPEYGEVTNVTTAVDIYSFGMCALEMAVLEIQGNGESSYVPQEAISSAIQLLEDPLQ
  REFIQKCLQSEPARRPTARELLFHPALFEVPSLKLLAAHCIVGHQHMIPENALEEITKNM
  DTSAVLAEIPAGPGREPVQTLYSQSPALELDKFLEDVRNGIYPLTAFGLPRPQQPQQEEV
  TSPVVPPSVKTPTPEPAEVETRKVVLMQCNIESVEEGVKHHLTLLLKLEDKLNRHLSCDL
  MPNENIPELAAELVQLGFISEADQSRLTSLLEETLNKFNFARNSTLNSAAVTVSS
• Function: Required for embryonic development. Plays a role in intestinal epithelial cell fate and proliferation, thereby involved in the architectural development of the intestine potentially via the regulation of Wnt-responsive genes. May play a role in subcellular trafficking between the endoplasmic reticulum and Golgi apparatus through interactions with the Rho-type GTPases. Binding to the NS3 protein of dengue virus type 2 appears to subvert this activity into the alteration of the intracellular membrane structure associated with flaviviral replication.
• Tissue Specificity: Ubiquitously expressed in all tissues examined with high levels in the testis.
• Reactome Pathway: Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Gout	DISHC0U7	Strong	Genetic Variation	[3]
Myeloid leukaemia	DISMN944	Strong	Posttranslational Modification	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Oral cancer	DISLD42D	Strong	Biomarker	[6]
Oral cavity carcinoma	DISZXMVL	Strong	Biomarker	[6]
Benign prostatic hyperplasia	DISI3CW2	moderate	Altered Expression	[7]
Prostate cancer	DISF190Y	moderate	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[7]
Bladder cancer	DISUHNM0	Limited	Biomarker	[5]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[5]

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 Nuclear receptor-binding protein (NRBP1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Nuclear receptor-binding protein (NRBP1).	[14]

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 protein (NRBP1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nuclear receptor-binding protein (NRBP1).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Nuclear receptor-binding protein (NRBP1).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nuclear receptor-binding protein (NRBP1).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Nuclear receptor-binding protein (NRBP1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nuclear receptor-binding protein (NRBP1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 affects the binding of Nuclear receptor-binding protein (NRBP1).	[15]

References

• [1] Identification of 22 novel loci associated withurinary biomarkers of albumin, sodium, andpotassium excretion.Kidney Int. 2019 May;95(5):1197-1208. doi: 10.1016/j.kint.2018.12.017. Epub 2019 Mar 12.
• [2] Nuclear receptor binding protein 1 correlates with better prognosis and induces caspase-dependent intrinsic apoptosis through the JNK signalling pathway in colorectal cancer.Cell Death Dis. 2018 Apr 1;9(4):436. doi: 10.1038/s41419-018-0402-7.
• [3] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [4] MADM, a novel adaptor protein that mediates phosphorylation of the 14-3-3 binding site of myeloid leukemia factor 1.J Biol Chem. 2002 Oct 25;277(43):40997-1008. doi: 10.1074/jbc.M206041200. Epub 2002 Aug 9.
• [5] High NRBP1 expression promotes proliferation and correlates with poor prognosis in bladder cancer.J Cancer. 2019 Jul 10;10(18):4270-4277. doi: 10.7150/jca.32656. eCollection 2019.
• [6] Integrated genomics approach to identify biologically relevant alterations in fewer samples.BMC Genomics. 2015 Nov 14;16:936. doi: 10.1186/s12864-015-2138-4.
• [7] High NRBP1 expression in prostate cancer is linked with poor clinical outcomes and increased cancer cell growth.Prostate. 2012 Nov;72(15):1678-87. doi: 10.1002/pros.22521. Epub 2012 Apr 2.
• [8] 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.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [14] 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.
• [15] "Minimalist" cyclopropene-containing photo-cross-linkers suitable for live-cell imaging and affinity-based protein labeling. J Am Chem Soc. 2014 Jul 16;136(28):9990-8. doi: 10.1021/ja502780z. Epub 2014 Jul 3.
• [16] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.