Details of Drug Off-Target (DOT)

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

• DOT Name: Nucleolin (NCL)
• Synonyms: Protein C23
• Gene Name: NCL
• UniProt ID: NUCL_HUMAN
• PDB ID: 2FC8; 2FC9; 2KRR
• Pfam ID: PF00076
• Sequence:
  MVKLAKAGKNQGDPKKMAPPPKEVEEDSEDEEMSEDEEDDSSGEEVVIPQKKGKKAAATS
  AKKVVVSPTKKVAVATPAKKAAVTPGKKAAATPAKKTVTPAKAVTTPGKKGATPGKALVA
  TPGKKGAAIPAKGAKNGKNAKKEDSDEEEDDDSEEDEEDDEDEDEDEDEIEPAAMKAAAA
  APASEDEDDEDDEDDEDDDDDEEDDSEEEAMETTPAKGKKAAKVVPVKAKNVAEDEDEEE
  DDEDEDDDDDEDDEDDDDEDDEEEEEEEEEEPVKEAPGKRKKEMAKQKAAPEAKKQKVEG
  TEPTTAFNLFVGNLNFNKSAPELKTGISDVFAKNDLAVVDVRIGMTRKFGYVDFESAEDL
  EKALELTGLKVFGNEIKLEKPKGKDSKKERDARTLLAKNLPYKVTQDELKEVFEDAAEIR
  LVSKDGKSKGIAYIEFKTEADAEKTFEEKQGTEIDGRSISLYYTGEKGQNQDYRGGKNST
  WSGESKTLVLSNLSYSATEETLQEVFEKATFIKVPQNQNGKSKGYAFIEFASFEDAKEAL
  NSCNKREIEGRAIRLELQGPRGSPNARSQPSKTLFVKGLSEDTTEETLKESFDGSVRARI
  VTDRETGSSKGFGFVDFNSEEDAKAAKEAMEDGEIDGNKVTLDWAKPKGEGGFGGRGGGR
  GGFGGRGGGRGGRGGFGGRGRGGFGGRGGFRGGRGGGGDHKPQGKKTKFE
• Function: Nucleolin is the major nucleolar protein of growing eukaryotic cells. It is found associated with intranucleolar chromatin and pre-ribosomal particles. It induces chromatin decondensation by binding to histone H1. It is thought to play a role in pre-rRNA transcription and ribosome assembly. May play a role in the process of transcriptional elongation. Binds RNA oligonucleotides with 5'-UUAGGG-3' repeats more tightly than the telomeric single-stranded DNA 5'-TTAGGG-3' repeats.
• KEGG Pathway: Pathogenic Escherichia coli infection (hsa05130)
• Reactome Pathway: Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)

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
Amsacrine	DMZKYIV	Approved	Nucleolin (NCL) affects the response to substance of Amsacrine.	[24]

5 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 Nucleolin (NCL).	[1]
G1	DMTV42K	Phase 1/2	G1 affects the phosphorylation of Nucleolin (NCL).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nucleolin (NCL).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Nucleolin (NCL).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Nucleolin (NCL).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nucleolin (NCL).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nucleolin (NCL).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Nucleolin (NCL).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Nucleolin (NCL).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nucleolin (NCL).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nucleolin (NCL).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Nucleolin (NCL).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nucleolin (NCL).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Nucleolin (NCL).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Nucleolin (NCL).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the splicing of Nucleolin (NCL).	[12]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Nucleolin (NCL).	[6]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Nucleolin (NCL).	[13]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of Nucleolin (NCL).	[14]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Nucleolin (NCL).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nucleolin (NCL).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the expression of Nucleolin (NCL).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nucleolin (NCL).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Nucleolin (NCL).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Itarnafloxin	DMCY9PO	Phase 2	Itarnafloxin affects the localization of Nucleolin (NCL).	[15]

References

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• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] 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.
• [7] 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.
• [8] Nucleophosmin in the pathogenesis of arsenic-related bladder carcinogenesis revealed by quantitative proteomics. Toxicol Appl Pharmacol. 2010 Jan 15;242(2):126-35. doi: 10.1016/j.taap.2009.09.016. Epub 2009 Oct 7.
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• [10] 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.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Incorporation of 5-fluorouracil into U2 snRNA blocks pseudouridylation and pre-mRNA splicing in vivo. Nucleic Acids Res. 2007;35(2):550-8. doi: 10.1093/nar/gkl1084. Epub 2006 Dec 14.
• [13] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
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• [18] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [19] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [20] 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.
• [21] 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.
• [22] 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.
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• [24] A novel interaction [corrected] of nucleolin with Rad51. Biochem Biophys Res Commun. 2006 May 26;344(1):206-13. doi: 10.1016/j.bbrc.2006.03.113. Epub 2006 Mar 29.