Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRVU0UA)

• DOT Name: Nuclear receptor coactivator 4 (NCOA4)
• Synonyms: NCoA-4; Androgen receptor coactivator 70 kDa protein; 70 kDa AR-activator; 70 kDa androgen receptor coactivator; Androgen receptor-associated protein of 70 kDa; Ret-activating protein ELE1
• Gene Name: NCOA4
• UniProt ID: NCOA4_HUMAN
• PDB ID: 1T5Z
• Pfam ID: PF12489
• Sequence:
  MNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHL
  ECLRSREVWLYEQVDLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSV
  CLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIQIPEHLMAHASSANIGPFLE
  KRGCISMPEQKSASGIVAVPFSEWLLGSKPASGYQAPYIPSTDPQDWLTQKQTLENSQTS
  SRACNFFNNVGGNLKGLENWLLKSEKSSYQKCNSHSTTSSFSIEMEKVGDQELPDQDEMD
  LSDWLVTPQESHKLRKPENGSRETSEKFKLLFQSYNVNDWLVKTDSCTNCQGNQPKGVEI
  ENLGNLKCLNDHLEAKKPLSTPSMVTEDWLVQNHQDPCKVEEVCRANEPCTSFAECVCDE
  NCEKEALYKWLLKKEGKDKNGMPVEPKPEPEKHKDSLNMWLCPRKEVIEQTKAPKAMTPS
  RIADSFQVIKNSPLSEWLIRPPYKEGSPKEVPGTEDRAGKQKFKSPMNTSWCSFNTADWV
  LPGKKMGNLSQLSSGEDKWLLRKKAQEVLLNSPLQEEHNFPPDHYGLPAVCDLFACMQLK
  VDKEKWLYRTPLQM
• Function: Enhances the androgen receptor transcriptional activity in prostate cancer cells. Ligand-independent coactivator of the peroxisome proliferator-activated receptor (PPAR) gamma.
• Tissue Specificity: Widely expressed. Also detected in adipose tissues and in different cell lines. Isoform Beta is only expressed in testis.
• KEGG Pathway:
  Ferroptosis (hsa04216)
  Pathways in cancer (hsa05200)
  Thyroid cancer (hsa05216)

Molecular Interaction Atlas (MIA) of This DOT

21 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 4 (NCOA4).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nuclear receptor coactivator 4 (NCOA4).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nuclear receptor coactivator 4 (NCOA4).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nuclear receptor coactivator 4 (NCOA4).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Nuclear receptor coactivator 4 (NCOA4).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nuclear receptor coactivator 4 (NCOA4).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Nuclear receptor coactivator 4 (NCOA4).	[7]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Nuclear receptor coactivator 4 (NCOA4).	[8]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Nuclear receptor coactivator 4 (NCOA4).	[10]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Nuclear receptor coactivator 4 (NCOA4).	[11]
Artesunate	DMR27C8	Approved	Artesunate decreases the expression of Nuclear receptor coactivator 4 (NCOA4).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Nuclear receptor coactivator 4 (NCOA4).	[13]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine increases the expression of Nuclear receptor coactivator 4 (NCOA4).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Nuclear receptor coactivator 4 (NCOA4).	[3]
ACYLINE	DM9GRTK	Phase 2	ACYLINE decreases the expression of Nuclear receptor coactivator 4 (NCOA4).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Nuclear receptor coactivator 4 (NCOA4).	[16]
Pifithrin-alpha	DM63OD7	Terminated	Pifithrin-alpha decreases the expression of Nuclear receptor coactivator 4 (NCOA4).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Nuclear receptor coactivator 4 (NCOA4).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Nuclear receptor coactivator 4 (NCOA4).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Nuclear receptor coactivator 4 (NCOA4).	[10]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Nuclear receptor coactivator 4 (NCOA4).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Nuclear receptor coactivator 4 (NCOA4).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Nuclear receptor coactivator 4 (NCOA4).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Nuclear receptor coactivator 4 (NCOA4).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Nuclear receptor coactivator 4 (NCOA4).	[9]

References

• [1] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [4] 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.
• [5] 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.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [8] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [9] 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.
• [10] Silibinin inhibits ethanol- or acetaldehyde-induced ferroptosis in liver cell lines. Toxicol In Vitro. 2022 Aug;82:105388. doi: 10.1016/j.tiv.2022.105388. Epub 2022 May 18.
• [11] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [12] Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway. Biomed Pharmacother. 2019 Jan;109:2043-2053. doi: 10.1016/j.biopha.2018.11.030. Epub 2018 Nov 26.
• [13] Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res. 1999 Dec 1;59(23):5892-5.
• [14] Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41.
• [15] 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.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] The vicious cycle between ferritinophagy and ROS production triggered EMT inhibition of gastric cancer cells was through p53/AKT/mTor pathway. Chem Biol Interact. 2020 Sep 1;328:109196. doi: 10.1016/j.cbi.2020.109196. Epub 2020 Jul 18.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] Impaired ferritinophagy flux induced by high fat diet mediates hepatic insulin resistance via endoplasmic reticulum stress. Food Chem Toxicol. 2020 Jun;140:111329. doi: 10.1016/j.fct.2020.111329. Epub 2020 Apr 10.