Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2CNBOG)

• DOT Name: Nuclear receptor coactivator 7 (NCOA7)
• Synonyms: 140 kDa estrogen receptor-associated protein; Estrogen nuclear receptor coactivator 1
• Gene Name: NCOA7
• Related Disease:
  Neoplasm
  Acute myocardial infarction
  Breast cancer
  Breast carcinoma
  Distal renal tubular acidosis
  Fibrosarcoma
  Hepatitis C virus infection
  Multiple sclerosis
  Prostate cancer
  Prostate neoplasm
  Neuroblastoma
  Squamous cell carcinoma
• UniProt ID: NCOA7_HUMAN
• PDB ID: 7OBP; 8AR6; 8AR9
• Pfam ID: PF01476 ; PF07534
• Sequence:
  MDTKEEKKERKQSYFARLKKKKQAKQNAETASAVATRTHTGKEDNNTVVLEPDKCNIAVE
  EEYMTDEKKKRKSNQLKEIRRTELKRYYSIDDNQNKTHDKKEKKMVVQKPHGTMEYTAGN
  QDTLNSIALKFNITPNKLVELNKLFTHTIVPGQVLFVPDANSPSSTLRLSSSSPGATVSP
  SSSDAEYDKLPDADLARKALKPIERVLSSTSEEDEPGVVKFLKMNCRYFTDGKGVVGGVM
  IVTPNNIMFDPHKSDPLVIENGCEEYGLICPMEEVVSIALYNDISHMKIKDALPSDLPQD
  LCPLYRPGEWEDLASEKDINPFSKFKSINKEKRQQNGEKIMTSDSRPIVPLEKSTGHTPT
  KPSGSSVSEKLKKLDSSRETSHGSPTVTKLSKEPSDTSSAFESTAKENFLGEDDDFVDLE
  ELSSQTGGGMHKKDTLKECLSLDPEERKKAESQINNSAVEMQVQSALAFLGTENDVELKG
  ALDLETCEKQDIMPEVDKQSGSPESRVENTLNIHEDLDKVKLIEYYLTKNKEGPQVSENL
  QKTELSDGKSIEPGGIDITLSSSLSQAGDPITEGNKEPDKTWVKKGEPLPVKLNSSTEAN
  VIKEALDSSLESTLDNSCQGAQMDNKSEVQLWLLKRIQVPIEDILPSKEEKSKTPPMFLC
  IKVGKPMRKSFATHTAAMVQQYGKRRKQPEYWFAVPRERVDHLYTFFVQWSPDVYGKDAK
  EQGFVVVEKEELNMIDNFFSEPTTKSWEIITVEEAKRRKSTCSYYEDEDEEVLPVLRPHS
  ALLENMHIEQLARRLPARVQGYPWRLAYSTLEHGTSLKTLYRKSASLDSPVLLVIKDMDN
  QIFGAYATHPFKFSDHYYGTGETFLYTFSPHFKVFKWSGENSYFINGDISSLELGGGGGR
  FGLWLDADLYHGRSNSCSTFNNDILSKKEDFIVQDLEVWAFD
• Function: Enhances the transcriptional activities of several nuclear receptors. Involved in the coactivation of different nuclear receptors, such as ESR1, THRB, PPARG and RARA.
• Tissue Specificity: Highly expressed in brain. Weakly expressed in mammary gland, ovary, uterus, prostate, stomach, bladder, spinal cord and pancreas. Expressed in cancer cell line.
• KEGG Pathway: Lysosome (hsa04142)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[1]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Distal renal tubular acidosis	DISP6CYE	Strong	Genetic Variation	[4]
Fibrosarcoma	DISWX7MU	Strong	Altered Expression	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[6]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[7]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[8]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[9]

4 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 Nuclear receptor coactivator 7 (NCOA7).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nuclear receptor coactivator 7 (NCOA7).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Nuclear receptor coactivator 7 (NCOA7).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Nuclear receptor coactivator 7 (NCOA7).	[28]

25 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 Nuclear receptor coactivator 7 (NCOA7).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nuclear receptor coactivator 7 (NCOA7).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear receptor coactivator 7 (NCOA7).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Nuclear receptor coactivator 7 (NCOA7).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nuclear receptor coactivator 7 (NCOA7).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Nuclear receptor coactivator 7 (NCOA7).	[19]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[20]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Nuclear receptor coactivator 7 (NCOA7).	[21]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[22]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Nuclear receptor coactivator 7 (NCOA7).	[23]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Nuclear receptor coactivator 7 (NCOA7).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[27]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[31]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[32]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Nuclear receptor coactivator 7 (NCOA7).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[33]
AM251	DMTAWHL	Investigative	AM251 increases the expression of Nuclear receptor coactivator 7 (NCOA7).	[34]

References

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• [2] Bioinformatics Analyses of Differentially Expressed Genes Associated with Acute Myocardial Infarction.Cardiovasc Ther. 2016 Apr;34(2):67-75. doi: 10.1111/1755-5922.12171.
• [3] A multistage association study identifies a breast cancer genetic locus at NCOA7.Cancer Res. 2011 Jun 1;71(11):3881-8. doi: 10.1158/0008-5472.CAN-10-2653. Epub 2011 May 24.
• [4] Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice.Am J Physiol Renal Physiol. 2018 Jul 1;315(1):F173-F185. doi: 10.1152/ajprenal.00407.2017. Epub 2018 Jan 31.
• [5] Induction of a unique isoform of the NCOA7 oxidation resistance gene by interferon -1b.J Interferon Cytokine Res. 2015 Mar;35(3):186-99. doi: 10.1089/jir.2014.0115. Epub 2014 Oct 20.
• [6] The interferon-inducible isoform of NCOA7 inhibits endosome-mediated viral entry.Nat Microbiol. 2018 Dec;3(12):1369-1376. doi: 10.1038/s41564-018-0273-9. Epub 2018 Nov 26.
• [7] Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.Nat Genet. 2018 May;50(5):682-692. doi: 10.1038/s41588-018-0086-z. Epub 2018 Apr 16.
• [8] ERAP140/Nbla10993 is a novel favorable prognostic indicator for neuroblastoma induced in response to retinoic acid.Oncol Rep. 2008 Jun;19(6):1381-8.
• [9] MALDI imaging reveals NCOA7 as a potential biomarker in oral squamous cell carcinoma arising from oral submucous fibrosis.Oncotarget. 2016 Sep 13;7(37):59987-60004. doi: 10.18632/oncotarget.11046.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [18] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [19] 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.
• [20] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [26] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [27] 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.
• [28] 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.
• [29] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [30] 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.
• [31] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [32] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [33] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [34] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.