Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1DGLQE)

• DOT Name: Importin-9 (IPO9)
• Synonyms: Imp9; Ran-binding protein 9; RanBP9
• Gene Name: IPO9
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Bone osteosarcoma
  Breast adenocarcinoma
  Breast cancer
  Breast carcinoma
  Neoplasm
  Osteosarcoma
  Schizophrenia
  Small-cell lung cancer
• UniProt ID: IPO9_HUMAN
• PDB ID: 6N1Z; 8F7A
• Pfam ID: PF03810
• Sequence:
  MAAAAAAGAASGLPGPVAQGLKEALVDTLTGILSPVQEVRAAAEEQIKVLEVTEEFGVHL
  AELTVDPQGALAIRQLASVILKQYVETHWCAQSEKFRPPETTERAKIVIRELLPNGLRES
  ISKVRSSVAYAVSAIAHWDWPEAWPQLFNLLMEMLVSGDLNAVHGAMRVLTEFTREVTDT
  QMPLVAPVILPEMYKIFTMAEVYGIRTRSRAVEIFTTCAHMICNMEELEKGAAKVLIFPV
  VQQFTEAFVQALQIPDGPTSDSGFKMEVLKAVTALVKNFPKHMVSSMQQILPIVWNTLTE
  SAAFYVRTEVNYTEEVEDPVDSDGEVLGFENLVFSIFEFVHALLENSKFKSTVKKALPEL
  IYYIILYMQITEEQIKVWTANPQQFVEDEDDDTFSYTVRIAAQDLLLAVATDFQNESAAA
  LAAAATRHLQEAEQTKNSGTEHWWKIHEACMLALGSVKAIITDSVKNGRIHFDMHGFLTN
  VILADLNLSVSPFLLGRALWAASRFTVAMSPELIQQFLQATVSGLHETQPPSVRISAVRA
  IWGYCDQLKVSESTHVLQPFLPSILDGLIHLAAQFSSEVLNLVMETLCIVCTVDPEFTAS
  MESKICPFTIAIFLKYSNDPVVASLAQDIFKELSQIEACQGPMQMRLIPTLVSIMQAPAD
  KIPAGLCATAIDILTTVVRNTKPPLSQLLICQAFPAVAQCTLHTDDNATMQNGGECLRAY
  VSVTLEQVAQWHDEQGHNGLWYVMQVVSQLLDPRTSEFTAAFVGRLVSTLISKAGRELGE
  NLDQILRAILSKMQQAETLSVMQSLIMVFAHLVHTQLEPLLEFLCSLPGPTGKPALEFVM
  AEWTSRQHLFYGQYEGKVSSVALCKLLQHGINADDKRLQDIRVKGEEIYSMDEGIRTRSK
  SAKNPERWTNIPLLVKILKLIINELSNVMEANAARQATPAEWSQDDSNDMWEDQEEEEEE
  EEDGLAGQLLSDILATSKYEEDYYEDDEEDDPDALKDPLYQIDLQAYLTDFLCQFAQQPC
  YIMFSGHLNDNERRVLQTIGI
• Function: Nuclear transport receptor that mediates nuclear import of proteins, such as histones, proteasome and actin. 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 import of pre-assembled proteasomes into the nucleus; AKIRIN2 acts as a molecular bridge between IPO9 and the proteasome complex. Mediates the nuclear import of histones H2A, H2B, H4 and H4. In addition to nuclear import, also acts as a chaperone for histones by preventing inappropriate non-nucleosomal interactions. Mediates the nuclear import of actin.
• 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
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[3]
Breast adenocarcinoma	DISMPHJ0	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[3]
Schizophrenia	DISSRV2N	Strong	Biomarker	[5]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Importin-9 (IPO9).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Importin-9 (IPO9).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Importin-9 (IPO9).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Importin-9 (IPO9).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Importin-9 (IPO9).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Importin-9 (IPO9).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Importin-9 (IPO9).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Importin-9 (IPO9).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Importin-9 (IPO9).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Importin-9 (IPO9).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Importin-9 (IPO9).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Importin-9 (IPO9).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Importin-9 (IPO9).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Importin-9 (IPO9).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Importin-9 (IPO9).	[14]

References

• [1] Differential Proteomic Analysis between Small Cell Lung Carcinoma (SCLC) and Pulmonary Carcinoid Tumors Reveals Molecular Signatures for Malignancy in Lung Cancer.Proteomics Clin Appl. 2018 Nov;12(6):e1800015. doi: 10.1002/prca.201800015. Epub 2018 Jul 5.
• [2] Enhanced tau pathology via RanBP9 and Hsp90/Hsc70 chaperone complexes.Hum Mol Genet. 2017 Oct 15;26(20):3973-3988. doi: 10.1093/hmg/ddx284.
• [3] RANBP9 suppresses tumor proliferation in colorectal cancer.Oncol Lett. 2019 May;17(5):4409-4416. doi: 10.3892/ol.2019.10134. Epub 2019 Mar 8.
• [4] Downregulation of importin-9 protects MCF-7 cells against apoptosis induced by the combination of garlic-derived alliin and paclitaxel.Oncol Rep. 2016 May;35(5):3084-93. doi: 10.3892/or.2016.4628. Epub 2016 Feb 22.
• [5] Investigating the potential genetic association between RANBP9 polymorphisms and the risk of schizophrenia.Mol Med Rep. 2015 Apr;11(4):2975-80. doi: 10.3892/mmr.2014.3045. Epub 2014 Dec 4.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] 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.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [15] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [16] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [17] 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.
• [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] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.