Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTBYYT0)

• DOT Name: Nucleophosmin (NPM1)
• Synonyms: NPM; Nucleolar phosphoprotein B23; Nucleolar protein NO38; Numatrin
• Gene Name: NPM1
• Related Disease: Dyskeratosis congenita
• UniProt ID: NPM_HUMAN
• PDB ID: 2LLH; 2P1B; 2VXD; 5EHD; 7OBG; 7OBH; 8AH2; 8AS5
• Pfam ID: PF16276 ; PF03066
• Sequence:
  MEDSMDMDMSPLRPQNYLFGCELKADKDYHFKVDNDENEHQLSLRTVSLGAGAKDELHIV
  EAEAMNYEGSPIKVTLATLKMSVQPTVSLGGFEITPPVVLRLKCGSGPVHISGQHLVAVE
  EDAESEDEEEEDVKLLSISGKRSAPGGGSKVPQKKVKLAADEDDDDDDEEDDDEDDDDDD
  FDDEEAEEKAPVKKSIRDTPAKNAQKSNQNGKDSKPSSTPRSKGQESFKKQEKTPKTPKG
  PSSVEDIKAKMQASIEKGGSLPKVEAKFINYVKNCFRMTDQEAIQDLWQWRKSL
• Function: Involved in diverse cellular processes such as ribosome biogenesis, centrosome duplication, protein chaperoning, histone assembly, cell proliferation, and regulation of tumor suppressors p53/TP53 and ARF. Binds ribosome presumably to drive ribosome nuclear export. Associated with nucleolar ribonucleoprotein structures and bind single-stranded nucleic acids. Acts as a chaperonin for the core histones H3, H2B and H4. Stimulates APEX1 endonuclease activity on apurinic/apyrimidinic (AP) double-stranded DNA but inhibits APEX1 endonuclease activity on AP single-stranded RNA. May exert a control of APEX1 endonuclease activity within nucleoli devoted to repair AP on rDNA and the removal of oxidized rRNA molecules. In concert with BRCA2, regulates centrosome duplication. Regulates centriole duplication: phosphorylation by PLK2 is able to trigger centriole replication. Negatively regulates the activation of EIF2AK2/PKR and suppresses apoptosis through inhibition of EIF2AK2/PKR autophosphorylation. Antagonizes the inhibitory effect of ATF5 on cell proliferation and relieves ATF5-induced G2/M blockade. In complex with MYC enhances the transcription of MYC target genes. May act as chaperonin or cotransporter in the nucleolar localization of transcription termination factor TTF1.
• Reactome Pathway:
  SUMOylation of transcription cofactors (R-HSA-3899300)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain (R-HSA-6804115)
  TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation (R-HSA-8869496)
  SARS-CoV-1-host interactions (R-HSA-9692914)
  ALK mutants bind TKIs (R-HSA-9700645)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  Nuclear events stimulated by ALK signaling in cancer (R-HSA-9725371)
  PKR-mediated signaling (R-HSA-9833482)
  Nuclear import of Rev protein (R-HSA-180746)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dyskeratosis congenita	DISSXV0K	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 9 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Nucleophosmin (NPM1) decreases the response to substance of Doxorubicin.	[11]
Fluorouracil	DMUM7HZ	Approved	Nucleophosmin (NPM1) decreases the response to substance of Fluorouracil.	[11]
Bortezomib	DMNO38U	Approved	Nucleophosmin (NPM1) increases the response to substance of Bortezomib.	[29]
Paclitaxel	DMLB81S	Approved	Nucleophosmin (NPM1) decreases the response to substance of Paclitaxel.	[11]
Gemcitabine	DMSE3I7	Approved	Nucleophosmin (NPM1) decreases the response to substance of Gemcitabine.	[11]
Docetaxel	DMDI269	Approved	Nucleophosmin (NPM1) decreases the response to substance of Docetaxel.	[11]
Josamycin	DMKJ8LB	Approved	Nucleophosmin (NPM1) affects the response to substance of Josamycin.	[30]
Pemetrexed	DMMX2E6	Approved	Nucleophosmin (NPM1) decreases the response to substance of Pemetrexed.	[11]
Vinorelbine	DMVXFYE	Approved	Nucleophosmin (NPM1) decreases the response to substance of Vinorelbine.	[11]

31 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 Nucleophosmin (NPM1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nucleophosmin (NPM1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nucleophosmin (NPM1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nucleophosmin (NPM1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nucleophosmin (NPM1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nucleophosmin (NPM1).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Nucleophosmin (NPM1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nucleophosmin (NPM1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Nucleophosmin (NPM1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Nucleophosmin (NPM1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Nucleophosmin (NPM1).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Nucleophosmin (NPM1).	[11]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Nucleophosmin (NPM1).	[6]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Nucleophosmin (NPM1).	[13]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Nucleophosmin (NPM1).	[14]
Etretinate	DM2CZFA	Approved	Etretinate increases the expression of Nucleophosmin (NPM1).	[14]
Isoflavone	DM7U58J	Phase 4	Isoflavone decreases the expression of Nucleophosmin (NPM1).	[5]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Nucleophosmin (NPM1).	[16]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Nucleophosmin (NPM1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Nucleophosmin (NPM1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nucleophosmin (NPM1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nucleophosmin (NPM1).	[19]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Nucleophosmin (NPM1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nucleophosmin (NPM1).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Nucleophosmin (NPM1).	[23]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Nucleophosmin (NPM1).	[24]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Nucleophosmin (NPM1).	[25]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Nucleophosmin (NPM1).	[26]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Nucleophosmin (NPM1).	[27]
Rutin	DMEHRAJ	Investigative	Rutin decreases the expression of Nucleophosmin (NPM1).	[28]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of Nucleophosmin (NPM1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine decreases the methylation of Nucleophosmin (NPM1).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Nucleophosmin (NPM1).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Nucleophosmin (NPM1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Nucleophosmin (NPM1).	[15]

References

• [1] Germline NPM1 mutations lead to altered rRNA 2'-O-methylation and cause dyskeratosis congenita. Nat Genet. 2019 Oct;51(10):1518-1529. doi: 10.1038/s41588-019-0502-z. Epub 2019 Sep 30.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation. EMBO Rep. 2007 Apr;8(4):394-400. doi: 10.1038/sj.embor.7400909. Epub 2007 Feb 23.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [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] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [9] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Proteomic identification of differentially expressed proteins associated with the multiple drug resistance in methotrexate-resistant human breast cancer cells. Int J Oncol. 2014 Jul;45(1):448-58.
• [12] Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia. Blood. 2008 Feb 15;111(4):2382-4. doi: 10.1182/blood-2007-07-103960. Epub 2007 Nov 30.
• [13] Decrease in nucleophosmin/B23 mRNA and telomerase activity during indomethacin-induced apoptosis of gastric KATO-III cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 1999 Dec;360(6):683-90. doi: 10.1007/s002109900145.
• [14] Consequences of the natural retinoid/retinoid X receptor ligands action in human breast cancer MDA-MB-231 cell line: Focus on functional proteomics. Toxicol Lett. 2017 Nov 5;281:26-34. doi: 10.1016/j.toxlet.2017.09.001. Epub 2017 Sep 5.
• [15] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [16] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [17] Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene. BMC Genomics. 2011 Jun 29;12:333.
• [18] The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene. 2016 Feb 18;35(7):833-45.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] 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.
• [21] Histone deacetylase inhibitor scriptaid induces cell cycle arrest and epigenetic change in colon cancer cells. Int J Oncol. 2008 Oct;33(4):767-76.
• [22] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [23] Deguelin, a selective silencer of the NPM1 mutant, potentiates apoptosis and induces differentiation in AML cells carrying the NPM1 mutation. Ann Hematol. 2015 Feb;94(2):201-10. doi: 10.1007/s00277-014-2206-x. Epub 2014 Sep 23.
• [24] 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.
• [25] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [26] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [27] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [28] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.
• [29] Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib. Leukemia. 2013 Oct;27(10):1970-80. doi: 10.1038/leu.2013.222. Epub 2013 Jul 23.
• [30] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.