Details of Drug Off-Target (DOT)

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

• DOT Name: Inhibitor of growth protein 3 (ING3)
• Synonyms: p47ING3
• Gene Name: ING3
• Related Disease:
  Adenocarcinoma
  Adenoma
  Carcinoma
  Colorectal adenoma
  Advanced cancer
  Head and neck cancer
  Head and neck carcinoma
  Head and neck neoplasm
  Head-neck squamous cell carcinoma
  Liver cancer
  Melanoma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Hepatocellular carcinoma
  Carcinoma of esophagus
  Castration-resistant prostate carcinoma
  Cutaneous melanoma
  Gastric cancer
  Lung carcinoma
  Stomach cancer
• UniProt ID: ING3_HUMAN
• PDB ID: 1X4I; 7ZMX
• Pfam ID: PF12998
• Sequence:
  MLYLEDYLEMIEQLPMDLRDRFTEMREMDLQVQNAMDQLEQRVSEFFMNAKKNKPEWREE
  QMASIKKDYYKALEDADEKVQLANQIYDLVDRHLRKLDQELAKFKMELEADNAGITEILE
  RRSLELDTPSQPVNNHHAHSHTPVEKRKYNPTSHHTTTDHIPEKKFKSEALLSTLTSDAS
  KENTLGCRNNNSTASSNNAYNVNSSQPLGSYNIGSLSSGTGAGAITMAAAQAVQATAQMK
  EGRRTSSLKASYEAFKNNDFQLGKEFSMARETVGYSSSSALMTTLTQNASSSAADSRSGR
  KSKNNNKSSSQQSSSSSSSSSLSSCSSSSTVVQEISQQTTVVPESDSNSQVDWTYDPNEP
  RYCICNQVSYGEMVGCDNQDCPIEWFHYGCVGLTEAPKGKWYCPQCTAAMKRRGSRHK
• Function: Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when directly recruited to sites of DNA damage. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome.
• Tissue Specificity: Expressed in brain, heart, kidney, liver, lung, ovaries, placenta, prostate, skeletal muscle, small intestine, spleen, testis and thymus.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Altered Expression	[1]
Adenoma	DIS78ZEV	Definitive	Altered Expression	[1]
Carcinoma	DISH9F1N	Definitive	Altered Expression	[1]
Colorectal adenoma	DISTSVHM	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[3]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[3]
Head and neck neoplasm	DIS1OB2G	Strong	Altered Expression	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[5]
Liver cancer	DISDE4BI	Strong	Therapeutic	[6]
Melanoma	DIS1RRCY	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[5]
Carcinoma of esophagus	DISS6G4D	Limited	Biomarker	[2]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Altered Expression	[9]
Cutaneous melanoma	DIS3MMH9	Limited	Altered Expression	[10]
Gastric cancer	DISXGOUK	Limited	Biomarker	[11]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[2]
Stomach cancer	DISKIJSX	Limited	Biomarker	[11]

17 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 Inhibitor of growth protein 3 (ING3).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Inhibitor of growth protein 3 (ING3).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inhibitor of growth protein 3 (ING3).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Inhibitor of growth protein 3 (ING3).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Inhibitor of growth protein 3 (ING3).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Inhibitor of growth protein 3 (ING3).	[17]
Thalidomide	DM70BU5	Approved	Thalidomide increases the expression of Inhibitor of growth protein 3 (ING3).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Inhibitor of growth protein 3 (ING3).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Inhibitor of growth protein 3 (ING3).	[20]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Inhibitor of growth protein 3 (ING3).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Inhibitor of growth protein 3 (ING3).	[23]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Inhibitor of growth protein 3 (ING3).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Inhibitor of growth protein 3 (ING3).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Inhibitor of growth protein 3 (ING3).	[26]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Inhibitor of growth protein 3 (ING3).	[27]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Inhibitor of growth protein 3 (ING3).	[28]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of Inhibitor of growth protein 3 (ING3).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Inhibitor of growth protein 3 (ING3).	[22]

References

• [1] Downregulated inhibitor of growth 3 (ING3) expression during colorectal carcinogenesis.Indian J Med Res. 2014 Apr;139(4):561-7.
• [2] Immunohistochemical profile of ING3 protein in normal and cancerous tissues.Oncol Lett. 2017 Mar;13(3):1631-1636. doi: 10.3892/ol.2017.5632. Epub 2017 Jan 23.
• [3] Tumor-specific mutation and downregulation of ING5 detected in oral squamous cell carcinoma.Int J Cancer. 2010 Nov 1;127(9):2088-94. doi: 10.1002/ijc.25224.
• [4] Downregulation of ING3 mRNA expression predicts poor prognosis in head and neck cancer.Cancer Sci. 2008 Mar;99(3):531-8. doi: 10.1111/j.1349-7006.2007.00708.x. Epub 2007 Dec 15.
• [5] ING3 is required for ATM signaling and DNA repair in response to DNA double strand breaks.Cell Death Differ. 2019 Nov;26(11):2344-2357. doi: 10.1038/s41418-019-0305-x. Epub 2019 Feb 25.
• [6] Molecular mechanisms of nano-selenium in mitigating hepatocellular carcinoma induced by N-nitrosodiethylamine (NDEA) in rats.Toxicol Mech Methods. 2014 Dec;24(8):593-602. doi: 10.3109/15376516.2014.956912. Epub 2014 Sep 4.
• [7] Human ex vivo prostate tissue model system identifies ING3 as an oncoprotein.Br J Cancer. 2018 Mar 6;118(5):713-726. doi: 10.1038/bjc.2017.447. Epub 2018 Jan 30.
• [8] Expression and prognostic value of ING3 in human primary hepatocellular carcinoma.Exp Biol Med (Maywood). 2012 Apr;237(4):352-61. doi: 10.1258/ebm.2011.011346.
• [9] ING3 is associated with increased cell invasion and lethal outcome in ERG-negative prostate cancer patients.Tumour Biol. 2016 Jul;37(7):9731-8. doi: 10.1007/s13277-016-4802-y. Epub 2016 Jan 23.
• [10] Prognostic significance of nuclear ING3 expression in human cutaneous melanoma.Clin Cancer Res. 2007 Jul 15;13(14):4111-6. doi: 10.1158/1078-0432.CCR-07-0408.
• [11] Inhibitor of growth 3 induces cell death by regulating cell proliferation, apoptosis and cell cycle arrest by blocking the PI3K/AKT pathway.Cancer Gene Ther. 2018 Oct;25(9-10):240-247. doi: 10.1038/s41417-018-0023-4. Epub 2018 Jun 1.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [16] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [17] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [18] Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce oxidative stress in cancer cells. Lipids Health Dis. 2010 Jun 2;9:56. doi: 10.1186/1476-511X-9-56.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [21] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [22] 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.
• [23] 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.
• [24] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [25] 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.
• [26] 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.
• [27] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [28] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [29] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.