Details of Drug Off-Target (DOT)

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

• DOT Name: Interferon regulatory factor 2-binding protein 2 (IRF2BP2)
• Synonyms: IRF-2-binding protein 2; IRF-2BP2
• Gene Name: IRF2BP2
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Cognitive impairment
  Gastric cancer
  Liver cancer
  Stomach cancer
  Arteriosclerosis
  Atherosclerosis
  Fatty liver disease
  Metabolic disorder
  Non-alcoholic fatty liver disease
  Promyelocytic leukaemia
  Stroke
  Common variable immunodeficiency
  Coronary atherosclerosis
  Coronary heart disease
  Immunodeficiency, common variable, 14
  Myocardial ischemia
• UniProt ID: I2BP2_HUMAN
• Pfam ID: PF11261
• Sequence:
  MAAAVAVAAASRRQSCYLCDLPRMPWAMIWDFTEPVCRGCVNYEGADRVEFVIETARQLK
  RAHGCFPEGRSPPGAAASAAAKPPPLSAKDILLQQQQQLGHGGPEAAPRAPQALERYPLA
  AAAERPPRLGSDFGSSRPAASLAQPPTPQPPPVNGILVPNGFSKLEEPPELNRQSPNPRR
  GHAVPPTLVPLMNGSATPLPTALGLGGRAAASLAAVSGTAAASLGSAQPTDLGAHKRPAS
  VSSSAAVEHEQREAAAKEKQPPPPAHRGPADSLSTAAGAAELSAEGAGKSRGSGEQDWVN
  RPKTVRDTLLALHQHGHSGPFESKFKKEPALTAGRLLGFEANGANGSKAVARTARKRKPS
  PEPEGEVGPPKINGEAQPWLSTSTEGLKIPMTPTSSFVSPPPPTASPHSNRTTPPEAAQN
  GQSPMAALILVADNAGGSHASKDANQVHSTTRRNSNSPPSPSSMNQRRLGPREVGGQGAG
  NTGGLEPVHPASLPDSSLATSAPLCCTLCHERLEDTHFVQCPSVPSHKFCFPCSRQSIKQ
  QGASGEVYCPSGEKCPLVGSNVPWAFMQGEIATILAGDVKVKKERDS
• Function: Acts as a transcriptional corepressor in a IRF2-dependent manner; this repression is not mediated by histone deacetylase activities. Represses the NFAT1-dependent transactivation of NFAT-responsive promoters. Acts as a coactivator of VEGFA expression in cardiac and skeletal muscles. Plays a role in immature B-cell differentiation.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Biomarker	[1]
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[2]
Gastric cancer	DISXGOUK	Definitive	Altered Expression	[3]
Liver cancer	DISDE4BI	Definitive	Biomarker	[1]
Stomach cancer	DISKIJSX	Definitive	Altered Expression	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[5]
Metabolic disorder	DIS71G5H	Strong	Altered Expression	[5]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[5]
Promyelocytic leukaemia	DISYGG13	Strong	Genetic Variation	[6]
Stroke	DISX6UHX	moderate	Biomarker	[7]
Common variable immunodeficiency	DISHE7JQ	Limited	Biomarker	[8]
Coronary atherosclerosis	DISKNDYU	Limited	Altered Expression	[9]
Coronary heart disease	DIS5OIP1	Limited	Altered Expression	[9]
Immunodeficiency, common variable, 14	DISSOD3T	Limited	Autosomal dominant	[10]
Myocardial ischemia	DISFTVXF	Limited	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[17]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[18]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[19]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[27]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[28]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Interferon regulatory factor 2-binding protein 2 (IRF2BP2).	[29]

References

• [1] The Tumor Suppressor Interferon Regulatory Factor 2 Binding Protein 2 Regulates Hippo Pathway in Liver Cancer by a Feedback Loop in Mice.Hepatology. 2020 Jun;71(6):1988-2004. doi: 10.1002/hep.30961. Epub 2020 Feb 16.
• [2] Suppressing Irf2bp2 expressions accelerates metabolic syndrome-associated brain injury and hepatic dyslipidemia.Biochem Biophys Res Commun. 2018 Sep 10;503(3):1651-1658. doi: 10.1016/j.bbrc.2018.07.095. Epub 2018 Aug 18.
• [3] Down-regulation of interferon regulatory factor 2 binding protein 2 suppresses gastric cancer progression by negatively regulating connective tissue growth factor.J Cell Mol Med. 2019 Dec;23(12):8076-8089. doi: 10.1111/jcmm.14677. Epub 2019 Sep 27.
• [4] Loss of IRF2BP2 in Microglia Increases Inflammation and Functional Deficits after Focal Ischemic Brain Injury.Front Cell Neurosci. 2017 Jul 19;11:201. doi: 10.3389/fncel.2017.00201. eCollection 2017.
• [5] Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3.Hepatology. 2020 May;71(5):1592-1608. doi: 10.1002/hep.30950. Epub 2020 Jan 30.
• [6] A rare case of acute promyelocytic leukemia with IRF2BP2-RARA fusion; and literature review.Onco Targets Ther. 2019 Aug 2;12:6157-6163. doi: 10.2147/OTT.S217622. eCollection 2019.
• [7] Interferon regulatory factor 2 binding protein 2: a new player of the innate immune response for stroke recovery.Neural Regen Res. 2017 Nov;12(11):1762-1764. doi: 10.4103/1673-5374.219026.
• [8] Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder. J Allergy Clin Immunol. 2016 Aug;138(2):544-550.e4. doi: 10.1016/j.jaci.2016.01.018. Epub 2016 Mar 23.
• [9] IRF2BP2 Reduces Macrophage Inflammation and Susceptibility to Atherosclerosis.Circ Res. 2015 Sep 25;117(8):671-83. doi: 10.1161/CIRCRESAHA.114.305777. Epub 2015 Jul 20.
• [10] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [19] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [25] 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.
• [26] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [29] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.