Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN2TL6N)

• DOT Name: NEDD4-binding protein 1 (N4BP1)
• Synonyms: N4BP1; EC 3.1.-.-
• Gene Name: N4BP1
• Related Disease:
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Rheumatoid arthritis
  MALT lymphoma
  Neuroblastoma
• UniProt ID: N4BP1_HUMAN
• PDB ID: 6Q3V
• EC Number: 3.1.-.-
• Pfam ID: PF11977
• Sequence:
  MAARAVLDEFTAPAEKAELLEQSRGRIEGLFGVSLAVLGALGAEEPLPARIWLQLCGAQE
  AVHSAKEYIKGICEPELEERECYPKDMHCIFVGAESLFLKSLIQDTCADLCILDIGLLGI
  RGSAEAVVMARSHIQQFVKLFENKENLPSSQKESEVKREFKQFVEAHADNYTMDLLILPT
  SLKKELLTLTQGEENLFETGDDEVIEMRDSQQTEFTQNAATGLNISRDETVLQEEARNKA
  GTPVSELTKQMDTVLSSSPDVLFDPINGLTPDEEALSNERICQKRRFSDSEERHTKKQFS
  LENVQEGEILHDAKTLAGNVIADLSDSSADSENLSPDIKETTEEMEYNILVNFFKTMGYS
  QEIVEKVIKVYGPSTEPLLLLEEIEKENKRFQEDREFSAGTVYPETNKTKNKGVYSSTNE
  LTTDSTPKKTQAHTQQNMVEKFSQLPFKVEAKPCTSNCRINTFRTVPIEQKHEVWGSNQN
  YICNTDPETDGLSPSVASPSPKEVNFVSRGASSHQPRVPLFPENGLHQQPEPLLPNNMKS
  ACEKRLGCCSSPHSKPNCSTLSPPMPLPQLLPSVTDARSAGPSDHIDSSVTGVQRFRDTL
  KIPYKLELKNEPGRTDLKHIVIDGSNVAITHGLKKFFSCRGIAIAVEYFWKLGNRNITVF
  VPQWRTRRDPNVTEQHFLTQLQELGILSLTPARMVFGERIASHDDRFLLHLADKTGGIIV
  TNDNFREFVNESVSWREIITKRLLQYTFVGDIFMVPDDPLGRSGPRLEEFLQKEVCLRDM
  QPLLSALPNVGMFDPSFRVPGTQAASTSHQPPTRIQGAPSSHWLPQQPHFPLLPALPSLQ
  QNLPMPAQRSSAETNELREALLKIFPDSEQRLKIDQILVAHPYMKDLNALSAMVLD
• Function: Potent suppressor of cytokine production that acts as a regulator of innate immune signaling and inflammation. Acts as a key negative regulator of select cytokine and chemokine responses elicited by TRIF-independent Toll-like receptors (TLRs), thereby limiting inflammatory cytokine responses to minor insults. In response to more threatening pathogens, cleaved by CASP8 downstream of TLR3 or TLR4, leading to its inactivation, thereby allowing production of inflammatory cytokines. Acts as a restriction factor against some viruses, such as HIV-1: restricts HIV-1 replication by binding to HIV-1 mRNAs and mediating their degradation via its ribonuclease activity. Also acts as an inhibitor of the E3 ubiquitin-protein ligase ITCH: acts by interacting with the second WW domain of ITCH, leading to compete with ITCH's substrates and impairing ubiquitination of substrates.
• Tissue Specificity: Detected in heart, lung, brain, liver, skeletal muscle, pancreas, kidney, spleen, testis and ovary.
• Reactome Pathway: Regulation of NF-kappa B signaling (R-HSA-9758274)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[1]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[1]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[2]
MALT lymphoma	DIS1AVVE	Limited	Biomarker	[3]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[4]

14 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 NEDD4-binding protein 1 (N4BP1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of NEDD4-binding protein 1 (N4BP1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NEDD4-binding protein 1 (N4BP1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of NEDD4-binding protein 1 (N4BP1).	[8]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of NEDD4-binding protein 1 (N4BP1).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of NEDD4-binding protein 1 (N4BP1).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of NEDD4-binding protein 1 (N4BP1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NEDD4-binding protein 1 (N4BP1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of NEDD4-binding protein 1 (N4BP1).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of NEDD4-binding protein 1 (N4BP1).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NEDD4-binding protein 1 (N4BP1).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of NEDD4-binding protein 1 (N4BP1).	[10]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of NEDD4-binding protein 1 (N4BP1).	[19]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of NEDD4-binding protein 1 (N4BP1).	[20]

4 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 increases the methylation of NEDD4-binding protein 1 (N4BP1).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of NEDD4-binding protein 1 (N4BP1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NEDD4-binding protein 1 (N4BP1).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of NEDD4-binding protein 1 (N4BP1).	[14]

References

• [1] [Corrigendum] miR-28-5p promotes the development and progression of ovarian cancer through inhibition of N4BP1.Int J Oncol. 2017 Jun;50(6):2236. doi: 10.3892/ijo.2017.3977. Epub 2017 Apr 27.
• [2] Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis.Pharmacogenomics J. 2013 Jun;13(3):235-41. doi: 10.1038/tpj.2012.8. Epub 2012 Apr 10.
• [3] N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation.Nat Microbiol. 2019 Sep;4(9):1532-1544. doi: 10.1038/s41564-019-0460-3. Epub 2019 May 27.
• [4] Nedd4-Binding Protein 1 and TNFAIP3-Interacting Protein 1 Control MHC-1 Display in Neuroblastoma.Cancer Res. 2018 Dec 1;78(23):6621-6631. doi: 10.1158/0008-5472.CAN-18-0545. Epub 2018 Sep 13.
• [5] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [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] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [9] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] 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.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] 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.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [17] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.
• [20] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.