Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG19WN0)

• DOT Name: Importin-11 (IPO11)
• Synonyms: Imp11; Ran-binding protein 11; RanBP11
• Gene Name: IPO11
• Related Disease:
  Non-insulin dependent diabetes
  Alcohol dependence
  Attention deficit hyperactivity disorder
  Lung neoplasm
  Neoplasm
  Bladder cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Acute myelogenous leukaemia
  Lung cancer
• UniProt ID: IPO11_HUMAN
• Pfam ID: PF03810
• Sequence:
  MDLNSASTVVLQVLTQATSQDTAVLKPAEEQLKQWETQPGFYSVLLNIFTNHTLDINVRW
  LAVLYFKHGIDRYWRRVAPHALSEEEKTTLRAGLITNFNEPINQIATQIAVLIAKVARLD
  CPRQWPELIPTLIESVKVQDDLRQHRALLTFYHVTKTLASKRLAADRKLFYDLASGIYNF
  ACSLWNHHTDTFLQEVSSGNEAAILSSLERTLLSLKVLRKLTVNGFVEPHKNMEVMGFLH
  GIFERLKQFLECSRSIGTDNVCRDRLEKTIILFTKVLLDFLDQHPFSFTPLIQRSLEFSV
  SYVFTEVGEGVTFERFIVQCMNLIKMIVKNYAYKPSKNFEDSSPETLEAHKIKMAFFTYP
  TLTEICRRLVSHYFLLTEEELTMWEEDPEGFTVEETGGDSWKYSLRPCTEVLFIDIFHEY
  NQTLTPVLLEMMQTLQGPTNVEDMNALLIKDAVYNAVGLAAYELFDSVDFDQWFKNQLLP
  ELQVIHNRYKPLRRRVIWLIGQWISVKFKSDLRPMLYEAICNLLQDQDLVVRIETATTLK
  LTVDDFEFRTDQFLPYLETMFTLLFQLLQQVTECDTKMHVLHVLSCVIERVNMQIRPYVG
  CLVQYLPLLWKQSEEHNMLRCAILTTLIHLVQGLGADSKNLYPFLLPVIQLSTDVSQPPH
  VYLLEDGLELWLVTLENSPCITPELLRIFQNMSPLLELSSENLRTCFKIINGYIFLSSTE
  FLQTYAVGLCQSFCELLKEITTEGQVQVLKVVENALKVNPILGPQMFQPILPYVFKGIIE
  GERYPVVMSTYLGVMGRVLLQNTSFFSSLLNEMAHKFNQEMDQLLGNMIEMWVDRMDNIT
  QPERRKLSALALLSLLPSDNSVIQDKFCGIINISVEGLHDVMTEDPETGTYKDCMLMSHL
  EEPKVTEDEEPPTEQDKRKKMLALKDPVHTVSLQQFIYEKLKAQQEMLGEQGFQSLMETV
  DTEIVTQLQEFLQGF
• Function: Functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin 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 the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. 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 the nuclear import of UBE2E3, and of RPL12.
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Altered Expression	[1]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[3]
Lung neoplasm	DISVARNB	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Bladder cancer	DISUHNM0	moderate	Altered Expression	[5]
Urinary bladder cancer	DISDV4T7	moderate	Altered Expression	[5]
Urinary bladder neoplasm	DIS7HACE	moderate	Altered Expression	[5]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[6]
Lung cancer	DISCM4YA	Limited	Biomarker	[7]

1 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 Importin-11 (IPO11).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Importin-11 (IPO11).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Importin-11 (IPO11).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Importin-11 (IPO11).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Importin-11 (IPO11).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Importin-11 (IPO11).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Importin-11 (IPO11).	[14]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Importin-11 (IPO11).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Importin-11 (IPO11).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Importin-11 (IPO11).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Importin-11 (IPO11).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Importin-11 (IPO11).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Importin-11 (IPO11).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Importin-11 (IPO11).	[21]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Importin-11 (IPO11).	[22]

References

• [1] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [2] Genome-wide significant association signals in IPO11-HTR1A region specific for alcohol and nicotine codependence.Alcohol Clin Exp Res. 2013 May;37(5):730-9. doi: 10.1111/acer.12032. Epub 2012 Dec 6.
• [3] Significant association between rare IPO11-HTR1A variants and attention deficit hyperactivity disorder in Caucasians.Am J Med Genet B Neuropsychiatr Genet. 2015 Oct;168(7):544-56. doi: 10.1002/ajmg.b.32329. Epub 2015 Jun 16.
• [4] The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein.J Cell Biol. 2017 Mar 6;216(3):641-656. doi: 10.1083/jcb.201604025. Epub 2017 Feb 13.
• [5] Importin-11 overexpression promotes the migration, invasion, and progression of bladder cancer associated with the deregulation of CDKN1A and THBS1.Urol Oncol. 2018 Jun;36(6):311.e1-311.e13. doi: 10.1016/j.urolonc.2018.03.001. Epub 2018 Mar 27.
• [6] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [7] Protecting PTEN in the Nucleus.Cancer Discov. 2017 Apr;7(4):OF1. doi: 10.1158/2159-8290.CD-NB2017-031. Epub 2017 Mar 3.
• [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] 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.
• [10] 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.
• [11] 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.
• [12] DNA microarray analysis of changes in gene expression induced by 1,25-dihydroxyvitamin D3 in human promyelocytic leukemia HL-60 cells. Biomed Res. 2006 Jun;27(3):99-109. doi: 10.2220/biomedres.27.99.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [15] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [22] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.