Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY1ZJXH)

• DOT Name: NF-kappa-B inhibitor beta (NFKBIB)
• Synonyms: NF-kappa-BIB; I-kappa-B-beta; IkB-B; IkB-beta; IkappaBbeta; Thyroid receptor-interacting protein 9; TR-interacting protein 9; TRIP-9
• Gene Name: NFKBIB
• Related Disease:
  Coeliac disease
  Gastric cancer
  Hepatitis C virus infection
  Influenza
  Stomach cancer
  Chronic obstructive pulmonary disease
  Epithelial ovarian cancer
  Gastrointestinal stromal tumour
  Ovarian cancer
  Ovarian neoplasm
  Rheumatoid arthritis
  Nasopharyngeal carcinoma
• UniProt ID: IKBB_HUMAN
• Pfam ID: PF00023 ; PF12796 ; PF13637
• Sequence:
  MAGVACLGKAADADEWCDSGLGSLGPDAAAPGGPGLGAELGPGLSWAPLVFGYVTEDGDT
  ALHLAVIHQHEPFLDFLLGFSAGTEYMDLQNDLGQTALHLAAILGETSTVEKLYAAGAGL
  CVAERRGHTALHLACRVGAHACARALLQPRPRRPREAPDTYLAQGPDRTPDTNHTPVALY
  PDSDLEKEEEESEEDWKLQLEAENYEGHTPLHVAVIHKDVEMVRLLRDAGADLDKPEPTC
  GRSPLHLAVEAQAADVLELLLRAGANPAARMYGGRTPLGSAMLRPNPILARLLRAHGAPE
  PEGEDEKSGPCSSSSDSDSGDEGDEYDDIVVHSSRSQTRLPPTPASKPLPDDPRPV
• Function: Inhibits NF-kappa-B by complexing with and trapping it in the cytoplasm. However, the unphosphorylated form resynthesized after cell stimulation is able to bind NF-kappa-B allowing its transport to the nucleus and protecting it to further NFKBIA-dependent inactivation. Association with inhibitor kappa B-interacting NKIRAS1 and NKIRAS2 prevent its phosphorylation rendering it more resistant to degradation, explaining its slower degradation.
• Tissue Specificity: Expressed in all tissues examined.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Cytosolic D.-sensing pathway (hsa04623)
  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)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Leishmaniasis (hsa05140)
  Toxoplasmosis (hsa05145)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Epstein-Barr virus infection (hsa05169)
  Coro.virus disease - COVID-19 (hsa05171)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway:
  RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476)
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coeliac disease	DISIY60C	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[3]
Influenza	DIS3PNU3	Strong	Altered Expression	[4]
Stomach cancer	DISKIJSX	Strong	Biomarker	[2]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Genetic Variation	[5]
Epithelial ovarian cancer	DIS56MH2	moderate	Genetic Variation	[6]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[7]
Ovarian cancer	DISZJHAP	moderate	Genetic Variation	[6]
Ovarian neoplasm	DISEAFTY	moderate	Genetic Variation	[6]
Rheumatoid arthritis	DISTSB4J	Disputed	Biomarker	[8]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[9]

9 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 NF-kappa-B inhibitor beta (NFKBIB).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NF-kappa-B inhibitor beta (NFKBIB).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NF-kappa-B inhibitor beta (NFKBIB).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of NF-kappa-B inhibitor beta (NFKBIB).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of NF-kappa-B inhibitor beta (NFKBIB).	[15]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of NF-kappa-B inhibitor beta (NFKBIB).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of NF-kappa-B inhibitor beta (NFKBIB).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of NF-kappa-B inhibitor beta (NFKBIB).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NF-kappa-B inhibitor beta (NFKBIB).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the degradation of NF-kappa-B inhibitor beta (NFKBIB).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN decreases the phosphorylation of NF-kappa-B inhibitor beta (NFKBIB).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NF-kappa-B inhibitor beta (NFKBIB).	[20]

References

• [1] Nuclear factor kappa B is activated in small intestinal mucosa of celiac patients.J Mol Med (Berl). 2003 Jun;81(6):373-9. doi: 10.1007/s00109-003-0440-0. Epub 2003 May 13.
• [2] miR-20a enhances cisplatin resistance of human gastric cancer cell line by targeting NFKBIB.Tumour Biol. 2016 Jan;37(1):1261-9. doi: 10.1007/s13277-015-3921-1. Epub 2015 Aug 20.
• [3] Hepatitis C virus core protein suppresses NF-kappaB activation and cyclooxygenase-2 expression by direct interaction with IkappaB kinase beta.J Virol. 2005 Jun;79(12):7648-57. doi: 10.1128/JVI.79.12.7648-7657.2005.
• [4] Upregulation of miRNA-4776 in Influenza Virus Infected Bronchial Epithelial Cells Is Associated with Downregulation of NFKBIB and Increased Viral Survival.Viruses. 2017 Apr 27;9(5):94. doi: 10.3390/v9050094.
• [5] Candidate genes for COPD in two large data sets.Eur Respir J. 2011 Feb;37(2):255-63. doi: 10.1183/09031936.00091709. Epub 2010 Jun 18.
• [6] Polymorphisms in NF-kappaB inhibitors and risk of epithelial ovarian cancer.BMC Cancer. 2009 Jun 6;9:170. doi: 10.1186/1471-2407-9-170.
• [7] Nuclear KIT induces a NFKBIB-RELA-KIT autoregulatory loop in imatinib-resistant gastrointestinal stromal tumors.Oncogene. 2019 Sep;38(38):6550-6565. doi: 10.1038/s41388-019-0900-9. Epub 2019 Jul 30.
• [8] Systematic review and meta-analysis: pharmacogenetics of anti-TNF treatment response in rheumatoid arthritis.Pharmacogenomics J. 2017 Oct;17(5):403-411. doi: 10.1038/tpj.2017.26. Epub 2017 Jun 13.
• [9] IKBB tumor suppressive role in nasopharyngeal carcinoma via NF-B-mediated signalling.Int J Cancer. 2016 Jan 1;138(1):160-70. doi: 10.1002/ijc.29702. Epub 2015 Aug 10.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] All-trans-retinoic acid induces manganese superoxide dismutase in human neuroblastoma through NF-kappaB. Free Radic Biol Med. 2008 Apr 15;44(8):1610-6. doi: 10.1016/j.freeradbiomed.2008.01.015. Epub 2008 Jan 30.
• [12] 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.
• [13] 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.
• [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] 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.
• [16] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [17] Baicalein inhibits the migration and invasive properties of human hepatoma cells. Toxicol Appl Pharmacol. 2011 Sep 15;255(3):316-26. doi: 10.1016/j.taap.2011.07.008. Epub 2011 Jul 23.
• [18] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [19] 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.
• [20] 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.