Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBT2HFL)

• DOT Name: Importin subunit beta-1 (KPNB1)
• Synonyms: Importin-90; Karyopherin subunit beta-1; Nuclear factor p97; Pore targeting complex 97 kDa subunit; PTAC97
• Gene Name: KPNB1
• UniProt ID: IMB1_HUMAN
• PDB ID: 1F59; 1IBR; 1M5N; 1O6O; 1O6P; 1QGK; 1QGR; 2P8Q; 2Q5D; 2QNA; 3LWW; 3W5K; 6N88; 6N89
• Pfam ID: PF13513 ; PF03810
• Sequence:
  MELITILEKTVSPDRLELEAAQKFLERAAVENLPTFLVELSRVLANPGNSQVARVAAGLQ
  IKNSLTSKDPDIKAQYQQRWLAIDANARREVKNYVLQTLGTETYRPSSASQCVAGIACAE
  IPVNQWPELIPQLVANVTNPNSTEHMKESTLEAIGYICQDIDPEQLQDKSNEILTAIIQG
  MRKEEPSNNVKLAATNALLNSLEFTKANFDKESERHFIMQVVCEATQCPDTRVRVAALQN
  LVKIMSLYYQYMETYMGPALFAITIEAMKSDIDEVALQGIEFWSNVCDEEMDLAIEASEA
  AEQGRPPEHTSKFYAKGALQYLVPILTQTLTKQDENDDDDDWNPCKAAGVCLMLLATCCE
  DDIVPHVLPFIKEHIKNPDWRYRDAAVMAFGCILEGPEPSQLKPLVIQAMPTLIELMKDP
  SVVVRDTAAWTVGRICELLPEAAINDVYLAPLLQCLIEGLSAEPRVASNVCWAFSSLAEA
  AYEAADVADDQEEPATYCLSSSFELIVQKLLETTDRPDGHQNNLRSSAYESLMEIVKNSA
  KDCYPAVQKTTLVIMERLQQVLQMESHIQSTSDRIQFNDLQSLLCATLQNVLRKVQHQDA
  LQISDVVMASLLRMFQSTAGSGGVQEDALMAVSTLVEVLGGEFLKYMEAFKPFLGIGLKN
  YAEYQVCLAAVGLVGDLCRALQSNIIPFCDEVMQLLLENLGNENVHRSVKPQILSVFGDI
  ALAIGGEFKKYLEVVLNTLQQASQAQVDKSDYDMVDYLNELRESCLEAYTGIVQGLKGDQ
  ENVHPDVMLVQPRVEFILSFIDHIAGDEDHTDGVVACAAGLIGDLCTAFGKDVLKLVEAR
  PMIHELLTEGRRSKTNKAKTLATWATKELRKLKNQA
• Function: Functions in nuclear protein import, either in association with an adapter protein, like an importin-alpha subunit, which binds to nuclear localization signals (NLS) in cargo substrates, or by acting as autonomous nuclear transport receptor. Acting autonomously, serves itself as NLS receptor. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Mediates autonomously the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5. In association with IPO7, mediates the nuclear import of H1 histone. In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones. In case of HIV-1 infection, binds and mediates the nuclear import of HIV-1 Rev. Imports SNAI1 and PRKCI into the nucleus.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  Apoptosis induced DNA fragmentation (R-HSA-140342)
  Regulation of cholesterol biosynthesis by SREBP (SREBF) (R-HSA-1655829)
  Transport of Ribonucleoproteins into the Host Nucleus (R-HSA-168271)
  NS1 Mediated Effects on Host Pathways (R-HSA-168276)
  Nuclear import of Rev protein (R-HSA-180746)
  Initiation of Nuclear Envelope (NE) Reformation (R-HSA-2995383)
  Neutrophil degranulation (R-HSA-6798695)
  Assembly of the ORC complex at the origin of replication (R-HSA-68616)
  Interferon alpha/beta signaling (R-HSA-909733)
  Postmitotic nuclear pore complex (NPC) reformation (R-HSA-9615933)
  Inhibition of nitric oxide production (R-HSA-9636249)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

23 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 Importin subunit beta-1 (KPNB1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Importin subunit beta-1 (KPNB1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Importin subunit beta-1 (KPNB1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Importin subunit beta-1 (KPNB1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Importin subunit beta-1 (KPNB1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Importin subunit beta-1 (KPNB1).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Importin subunit beta-1 (KPNB1).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Importin subunit beta-1 (KPNB1).	[2]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Importin subunit beta-1 (KPNB1).	[8]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Importin subunit beta-1 (KPNB1).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Importin subunit beta-1 (KPNB1).	[7]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Importin subunit beta-1 (KPNB1).	[5]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Importin subunit beta-1 (KPNB1).	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Importin subunit beta-1 (KPNB1).	[11]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Importin subunit beta-1 (KPNB1).	[12]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Importin subunit beta-1 (KPNB1).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Importin subunit beta-1 (KPNB1).	[9]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Importin subunit beta-1 (KPNB1).	[14]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Importin subunit beta-1 (KPNB1).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Importin subunit beta-1 (KPNB1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Importin subunit beta-1 (KPNB1).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Importin subunit beta-1 (KPNB1).	[18]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Importin subunit beta-1 (KPNB1).	[19]

2 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 Importin subunit beta-1 (KPNB1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Importin subunit beta-1 (KPNB1).	[16]

References

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• [2] Differentiation-associated alteration in gene expression of importins and exportins in human leukemia HL-60 cells. Biomed Res. 2008 Jun;29(3):141-5. doi: 10.2220/biomedres.29.141.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
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• [5] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [6] 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.
• [7] 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.
• [8] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [9] 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.
• [10] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [13] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [14] Gene expression-signature of belinostat in cell lines is specific for histone deacetylase inhibitor treatment, with a corresponding signature in xenografts. Anticancer Drugs. 2009 Sep;20(8):682-92.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.