Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRC7DBJ)

• DOT Name: Exportin-1
• Synonyms: Exp1; Chromosome region maintenance 1 protein homolog
• Gene Name: XPO1
• UniProt ID: XPO1_HUMAN
• PDB ID: 1W9C; 2L1L; 3GB8; 4BSM; 4BSN; 5DIS; 6TVO; 7B51
• Pfam ID: PF08767 ; PF18777 ; PF18784 ; PF18787 ; PF03810 ; PF08389
• Sequence:
  MPAIMTMLADHAARQLLDFSQKLDINLLDNVVNCLYHGEGAQQRMAQEVLTHLKEHPDAW
  TRVDTILEFSQNMNTKYYGLQILENVIKTRWKILPRNQCEGIKKYVVGLIIKTSSDPTCV
  EKEKVYIGKLNMILVQILKQEWPKHWPTFISDIVGASRTSESLCQNNMVILKLLSEEVFD
  FSSGQITQVKSKHLKDSMCNEFSQIFQLCQFVMENSQNAPLVHATLETLLRFLNWIPLGY
  IFETKLISTLIYKFLNVPMFRNVSLKCLTEIAGVSVSQYEEQFVTLFTLTMMQLKQMLPL
  NTNIRLAYSNGKDDEQNFIQNLSLFLCTFLKEHDQLIEKRLNLRETLMEALHYMLLVSEV
  EETEIFKICLEYWNHLAAELYRESPFSTSASPLLSGSQHFDVPPRRQLYLPMLFKVRLLM
  VSRMAKPEEVLVVENDQGEVVREFMKDTDSINLYKNMRETLVYLTHLDYVDTERIMTEKL
  HNQVNGTEWSWKNLNTLCWAIGSISGAMHEEDEKRFLVTVIKDLLGLCEQKRGKDNKAII
  ASNIMYIVGQYPRFLRAHWKFLKTVVNKLFEFMHETHDGVQDMACDTFIKIAQKCRRHFV
  QVQVGEVMPFIDEILNNINTIICDLQPQQVHTFYEAVGYMIGAQTDQTVQEHLIEKYMLL
  PNQVWDSIIQQATKNVDILKDPETVKQLGSILKTNVRACKAVGHPFVIQLGRIYLDMLNV
  YKCLSENISAAIQANGEMVTKQPLIRSMRTVKRETLKLISGWVSRSNDPQMVAENFVPPL
  LDAVLIDYQRNVPAAREPEVLSTMAIIVNKLGGHITAEIPQIFDAVFECTLNMINKDFEE
  YPEHRTNFFLLLQAVNSHCFPAFLAIPPTQFKLVLDSIIWAFKHTMRNVADTGLQILFTL
  LQNVAQEEAAAQSFYQTYFCDILQHIFSVVTDTSHTAGLTMHASILAYMFNLVEEGKIST
  SLNPGNPVNNQIFLQEYVANLLKSAFPHLQDAQVKLFVTGLFSLNQDIPAFKEHLRDFLV
  QIKEFAGEDTSDLFLEEREIALRQADEEKHKRQMSVPGIFNPHEIPEEMCD
• Function: Mediates the nuclear export of cellular proteins (cargos) bearing a leucine-rich nuclear export signal (NES) and of RNAs. In the nucleus, in association with RANBP3, binds cooperatively to the NES on its target protein and to the GTPase RAN in its active GTP-bound form (Ran-GTP). Docking of this complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the cargo from the export receptor. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Involved in U3 snoRNA transport from Cajal bodies to nucleoli. Binds to late precursor U3 snoRNA bearing a TMG cap; (Microbial infection) Mediates the export of unspliced or incompletely spliced RNAs out of the nucleus from different viruses including HIV-1, HTLV-1 and influenza A. Interacts with, and mediates the nuclear export of HIV-1 Rev and HTLV-1 Rex proteins. Involved in HTLV-1 Rex multimerization.
• Tissue Specificity: Expressed in heart, brain, placenta, lung, liver, skeletal muscle, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes. Not expressed in the kidney.
• KEGG Pathway:
  Ribosome biogenesis in eukaryotes (hsa03008)
  Nucleocytoplasmic transport (hsa03013)
  Viral life cycle - HIV-1 (hsa03250)
  Influenza A (hsa05164)
  Human T-cell leukemia virus 1 infection (hsa05166)
• Reactome Pathway:
  Rev-mediated nuclear export of HIV RNA (R-HSA-165054)
  NEP/NS2 Interacts with the Cellular Export Machinery (R-HSA-168333)
  Downregulation of TGF-beta receptor signaling (R-HSA-2173788)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  HuR (ELAVL1) binds and stabilizes mRNA (R-HSA-450520)
  RHO GTPases Activate Formins (R-HSA-5663220)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Mitotic Prometaphase (R-HSA-68877)
  Cyclin A/B1/B2 associated events during G2/M transition (R-HSA-69273)
  Estrogen-dependent nuclear events downstream of ESR-membrane signaling (R-HSA-9634638)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Heme signaling (R-HSA-9707616)
  NPAS4 regulates expression of target genes (R-HSA-9768919)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Piperlongumine	DMIZCOE	Preclinical	Exportin-1 decreases the response to substance of Piperlongumine.	[18]

17 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 Exportin-1.	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Exportin-1.	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Exportin-1.	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Exportin-1.	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Exportin-1.	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Exportin-1.	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Exportin-1.	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Exportin-1.	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Exportin-1.	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Exportin-1.	[3]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Exportin-1.	[9]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Exportin-1.	[10]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Exportin-1.	[3]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Exportin-1.	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Exportin-1.	[15]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Exportin-1.	[16]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 decreases the expression of Exportin-1.	[17]

4 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 affects the methylation of Exportin-1.	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Exportin-1.	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Exportin-1.	[13]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Exportin-1.	[12]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [4] 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.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways. Int J Mol Sci. 2019 Nov 30;20(23):6039. doi: 10.3390/ijms20236039.
• [10] Effects of paclitaxel on proliferation and apoptosis in human acute myeloid leukemia HL-60 cells. Acta Pharmacol Sin. 2004 Mar;25(3):378-84.
• [11] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [12] 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.
• [13] 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.
• [14] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [15] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [16] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [17] 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [corrected] induces CRM1-dependent p53 nuclear accumulation in human bronchial epithelial cells. Toxicol Sci. 2010 Jul;116(1):206-15. doi: 10.1093/toxsci/kfq123. Epub 2010 Apr 26.
• [18] Piperlongumine is a novel nuclear export inhibitor with potent anticancer activity. Chem Biol Interact. 2015 Jul 25;237:66-72. doi: 10.1016/j.cbi.2015.05.016. Epub 2015 May 28.