Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLAYEL9)

• DOT Name: NF-kappa-B inhibitor epsilon (NFKBIE)
• Synonyms: NF-kappa-BIE; I-kappa-B-epsilon; IkB-E; IkB-epsilon; IkappaBepsilon
• Gene Name: NFKBIE
• Related Disease:
  Bacteremia
  Central nervous system lymphoma
  Classic Hodgkin lymphoma
  Follicular lymphoma
  Mediastinal large B-cell lymphoma
  Neoplasm
  Pneumococcal meningitis
  T-cell acute lymphoblastic leukaemia
  Advanced cancer
  B-cell neoplasm
  Hepatitis C virus infection
  Melanoma
  Rheumatoid arthritis
• UniProt ID: IKBE_HUMAN
• Pfam ID: PF12796
• Sequence:
  MNQRRSESRPGNHRLQAYAEPGKGDSGGAGPLSGSARRGRGGGGAIRVRRPCWSGGAGRG
  GGPAWAVRLPTVTAGWTWPALRTLSSLRAGPSEPHSPGRRPPRAGRPLCQADPQPGKAAR
  RSLEPDPAQTGPRPARAAGMSEARKGPDEAEESQYDSGIESLRSLRSLPESTSAPASGPS
  DGSPQPCTHPPGPVKEPQEKEDADGERADSTYGSSSLTYTLSLLGGPEAEDPAPRLPLPH
  VGALSPQQLEALTYISEDGDTLVHLAVIHEAPAVLLCCLALLPQEVLDIQNNLYQTALHL
  AVHLDQPGAVRALVLKGASRALQDRHGDTALHVACQRQHLACARCLLEGRPEPGRGTSHS
  LDLQLQNWQGLACLHIATLQKNQPLMELLLRNGADIDVQEGTSGKTALHLAVETQERGLV
  QFLLQAGAQVDARMLNGCTPLHLAAGRGLMGISSTLCKAGADSLLRNVEDETPQDLTEES
  LVLLPFDDLKISGKLLLCTD
• Function: Inhibits NF-kappa-B by complexing with and trapping it in the cytoplasm. Inhibits DNA-binding of NF-kappa-B p50-p65 and p50-c-Rel complexes.
• Tissue Specificity: Highly expressed in spleen, testis and lung, followed by kidney, pancreas, heart, placenta and brain. Also expressed in granulocytes and macrophages.
• KEGG Pathway:
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
  Neurotrophin sig.ling pathway (hsa04722)
  Adipocytokine sig.ling pathway (hsa04920)
  Epstein-Barr virus infection (hsa05169)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway: Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacteremia	DIS6N9RZ	Definitive	Genetic Variation	[1]
Central nervous system lymphoma	DISBYQTA	Definitive	Genetic Variation	[2]
Classic Hodgkin lymphoma	DISV1LU6	Definitive	Genetic Variation	[2]
Follicular lymphoma	DISVEUR6	Definitive	Genetic Variation	[2]
Mediastinal large B-cell lymphoma	DISAUA10	Definitive	Biomarker	[2]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Pneumococcal meningitis	DISM5U0L	Definitive	Genetic Variation	[1]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[4]
Melanoma	DIS1RRCY	moderate	Biomarker	[5]
Rheumatoid arthritis	DISTSB4J	moderate	Altered Expression	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	NF-kappa-B inhibitor epsilon (NFKBIE) decreases the response to substance of Arsenic.	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[17]
Menadione	DMSJDTY	Approved	Menadione affects the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[15]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[19]
Gemcitabine	DMSE3I7	Approved	Gemcitabine affects the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[21]
Rigosertib	DMOSTXF	Phase 3	Rigosertib affects the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[22]
HMPL-004	DM29XGY	Phase 3	HMPL-004 increases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[23]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl increases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[27]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[23]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of NF-kappa-B inhibitor epsilon (NFKBIE).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bortezomib	DMNO38U	Approved	Bortezomib increases the stability of NF-kappa-B inhibitor epsilon (NFKBIE).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of NF-kappa-B inhibitor epsilon (NFKBIE).	[25]

References

• [1] Genetic Variation in NFKBIE Is Associated With Increased Risk of Pneumococcal Meningitis in Children.EBioMedicine. 2015 Dec 2;3:93-99. doi: 10.1016/j.ebiom.2015.11.048. eCollection 2016 Jan.
• [2] Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma.Blood. 2016 Dec 8;128(23):2666-2670. doi: 10.1182/blood-2016-03-704528. Epub 2016 Sep 26.
• [3] Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type.J Invest Dermatol. 2018 Nov;138(11):2365-2376. doi: 10.1016/j.jid.2018.04.038. Epub 2018 May 30.
• [4] Genetic variation in toll-like receptors and retinoic acid-inducible gene I and outcome of hepatitis C virus infection: a candidate gene association study.J Viral Hepat. 2014 Aug;21(8):578-84. doi: 10.1111/jvh.12188. Epub 2013 Nov 13.
• [5] Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway.Nat Genet. 2015 Oct;47(10):1194-9. doi: 10.1038/ng.3382. Epub 2015 Sep 7.
• [6] Impaired NFKBIE gene function decreases cellular uptake of methotrexate by down-regulating SLC19A1 expression in a human rheumatoid arthritis cell line.Mod Rheumatol. 2016 Jul;26(4):507-16. doi: 10.3109/14397595.2015.1112481. Epub 2016 Jan 4.
• [7] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [8] 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.
• [9] 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.
• [10] Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors. Toxicol In Vitro. 2015 Sep;29(6):1231-9. doi: 10.1016/j.tiv.2014.10.012. Epub 2014 Oct 24.
• [11] 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.
• [12] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [13] 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.
• [14] Synergistic antiproliferative effect of arsenic trioxide combined with bortezomib in HL60 cell line and primary blasts from patients affected by myeloproliferative disorders. Cancer Genet Cytogenet. 2010 Jun;199(2):110-20. doi: 10.1016/j.cancergencyto.2010.02.010.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Peripheral blood expression of nuclear factor-kappab-regulated genes is associated with rheumatoid arthritis disease activity and responds differentially to anti-tumor necrosis factor-alpha versus methotrexate. J Rheumatol. 2007 Sep;34(9):1817-22. Epub 2007 Aug 1.
• [17] 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.
• [18] Efficacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-I associated adult T-cell leukemia/lymphoma. Oncogene. 2005 Jan 13;24(3):419-30. doi: 10.1038/sj.onc.1208212.
• [19] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [20] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [23] Mapping the dynamics of Nrf2 antioxidant and NFB inflammatory responses by soft electrophilic chemicals in human liver cells defines the transition from adaptive to adverse responses. Toxicol In Vitro. 2022 Oct;84:105419. doi: 10.1016/j.tiv.2022.105419. Epub 2022 Jun 17.
• [24] 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.
• [25] 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.
• [26] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [29] Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol. 2008 Jan 15;226(2):199-205. doi: 10.1016/j.taap.2007.09.004. Epub 2007 Sep 15.