Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB5ZHC8)

• DOT Name: Nuclear pore complex protein Nup85 (NUP85)
• Synonyms: 85 kDa nucleoporin; FROUNT; Nucleoporin Nup75; Nucleoporin Nup85; Pericentrin-1
• Gene Name: NUP85
• Related Disease:
  Congestive heart failure
  Nephrotic syndrome, type 17
  Systemic sclerosis
  Immune system disorder
  Familial idiopathic steroid-resistant nephrotic syndrome
  Nephrotic syndrome, type 2
  Tourette syndrome
• UniProt ID: NUP85_HUMAN
• PDB ID: 5A9Q; 7PEQ; 7R5J; 7R5K
• Pfam ID: PF07575
• Sequence:
  MEELDGEPTVTLIPGVNSKKNQMYFDWGPGEMLVCETSFNKKEKSEMVPSCPFIYIIRKD
  VDVYSQILRKLFNESHGIFLGLQRIDEELTGKSRKSQLVRVSKNYRSVIRACMEEMHQVA
  IAAKDPANGRQFSSQVSILSAMELIWNLCEILFIEVAPAGPLLLHLLDWVRLHVCEVDSL
  SADVLGSENPSKHDSFWNLVTILVLQGRLDEARQMLSKEADASPASAGICRIMGDLMRTM
  PILSPGNTQTLTELELKWQHWHEECERYLQDSTFATSPHLESLLKIMLGDEAALLEQKEL
  LSNWYHFLVTRLLYSNPTVKPIDLHYYAQSSLDLFLGGESSPEPLDNILLAAFEFDIHQV
  IKECSIALSNWWFVAHLTDLLDHCKLLQSHNLYFGSNMREFLLLEYASGLFAHPSLWQLG
  VDYFDYCPELGRVSLELHIERIPLNTEQKALKVLRICEQRQMTEQVRSICKILAMKAVRN
  NRLGSALSWSIRAKDAAFATLVSDRFLRDYCERGCFSDLDLIDNLGPAMMLSDRLTFLGK
  YREFHRMYGEKRFADAASLLLSLMTSRIAPRSFWMTLLTDALPLLEQKQVIFSAEQTYEL
  MRCLEDLTSRRPVHGESDTEQLQDDDIETTKVEMLRLSLARNLARAIIREGSLEGS
• Function: Essential component of the nuclear pore complex (NPC) that seems to be required for NPC assembly and maintenance. As part of the NPC Nup107-160 subcomplex plays a role in RNA export and in tethering NUP96/Nup98 and NUP153 to the nucleus. The Nup107-160 complex seems to be required for spindle assembly during mitosis. NUP85 is required for membrane clustering of CCL2-activated CCR2. Seems to be involved in CCR2-mediated chemotaxis of monocytes and may link activated CCR2 to the phosphatidyl-inositol 3-kinase-Rac-lammellipodium protrusion cascade. Involved in nephrogenesis.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Amyotrophic lateral sclerosis (hsa05014)
• Reactome Pathway:
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)
  Transport of the SLBP independent Mature mRNA (R-HSA-159227)
  Transport of the SLBP Dependant Mature mRNA (R-HSA-159230)
  Transport of Mature mRNA Derived from an Intronless Transcript (R-HSA-159231)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)
  Rev-mediated nuclear export of HIV RNA (R-HSA-165054)
  Transport of Ribonucleoproteins into the Host Nucleus (R-HSA-168271)
  NS1 Mediated Effects on Host Pathways (R-HSA-168276)
  Viral Messenger RNA Synthesis (R-HSA-168325)
  NEP/NS2 Interacts with the Cellular Export Machinery (R-HSA-168333)
  Regulation of Glucokinase by Glucokinase Regulatory Protein (R-HSA-170822)
  Nuclear import of Rev protein (R-HSA-180746)
  Vpr-mediated nuclear import of PICs (R-HSA-180910)
  snRNP Assembly (R-HSA-191859)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of ubiquitinylation proteins (R-HSA-3232142)
  Nuclear Pore Complex (NPC) Disassembly (R-HSA-3301854)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  SUMOylation of SUMOylation proteins (R-HSA-4085377)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  SUMOylation of RNA binding proteins (R-HSA-4570464)
  SUMOylation of DNA replication proteins (R-HSA-4615885)
  Transcriptional regulation by small RNAs (R-HSA-5578749)
  Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) (R-HSA-5619107)
  RHO GTPases Activate Formins (R-HSA-5663220)
  tRNA processing in the nucleus (R-HSA-6784531)
  Mitotic Prometaphase (R-HSA-68877)
  HCMV Early Events (R-HSA-9609690)
  HCMV Late Events (R-HSA-9610379)
  Postmitotic nuclear pore complex (NPC) reformation (R-HSA-9615933)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Nephrotic syndrome, type 17	DIS1D0GZ	Strong	Autosomal recessive	[2]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[3]
Immune system disorder	DISAEGPH	moderate	Altered Expression	[4]
Familial idiopathic steroid-resistant nephrotic syndrome	DISQ53RS	Supportive	Autosomal dominant	[2]
Nephrotic syndrome, type 2	DISIRFO1	Disputed	GermlineCausalMutation	[2]
Tourette syndrome	DISX9D54	No Known	Unknown	[5]

12 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 Nuclear pore complex protein Nup85 (NUP85).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nuclear pore complex protein Nup85 (NUP85).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nuclear pore complex protein Nup85 (NUP85).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nuclear pore complex protein Nup85 (NUP85).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nuclear pore complex protein Nup85 (NUP85).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Nuclear pore complex protein Nup85 (NUP85).	[11]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Nuclear pore complex protein Nup85 (NUP85).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nuclear pore complex protein Nup85 (NUP85).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nuclear pore complex protein Nup85 (NUP85).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Nuclear pore complex protein Nup85 (NUP85).	[16]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Nuclear pore complex protein Nup85 (NUP85).	[17]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Nuclear pore complex protein Nup85 (NUP85).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Nuclear pore complex protein Nup85 (NUP85).	[15]

References

• [1] A novel activator of C-C chemokine, FROUNT, is expressed with C-C chemokine receptor 2 and its ligand in failing human heart.J Card Fail. 2007 Mar;13(2):114-9. doi: 10.1016/j.cardfail.2006.11.003.
• [2] Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. J Clin Invest. 2018 Oct 1;128(10):4313-4328. doi: 10.1172/JCI98688. Epub 2018 Sep 4.
• [3] GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.Nat Commun. 2019 Oct 31;10(1):4955. doi: 10.1038/s41467-019-12760-y.
• [4] Pivotal function for cytoplasmic protein FROUNT in CCR2-mediated monocyte chemotaxis.Nat Immunol. 2005 Aug;6(8):827-35. doi: 10.1038/ni1222. Epub 2005 Jul 3.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [13] BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res. 2014 Feb 15;20(4):912-25.
• [14] 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.
• [15] 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.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [17] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [18] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.