Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX4VY51)

• DOT Name: Insulin-induced gene 2 protein (INSIG2)
• Synonyms: INSIG-2
• Gene Name: INSIG2
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Cardiovascular disease
  Cerebrovascular disease
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal carcinoma
  Dilated cardiomyopathy 1A
  Familial hypercholesterolemia
  Familial multiple trichoepithelioma
  Invasive ductal breast carcinoma
  Non-alcoholic fatty liver disease
  Pancreatic cancer
  Peripheral vascular disease
  Polycystic ovarian syndrome
  Schizophrenia
  Split hand-foot malformation
  Type-1/2 diabetes
  Coronary atherosclerosis
  Asthma
  Neoplasm
• UniProt ID: INSI2_HUMAN
• PDB ID: 4J82; 6M49; 7ETW
• Pfam ID: PF07281
• Sequence:
  MAEGETESPGPKKCGPYISSVTSQSVNLMIRGVVLFFIGVFLALVLNLLQIQRNVTLFPP
  DVIASIFSSAWWVPPCCGTASAVIGLLYPCIDRHLGEPHKFKREWSSVMRCVAVFVGINH
  ASAKVDFDNNIQLSLTLAALSIGLWWTFDRSRSGFGLGVGIAFLATVVTQLLVYNGVYQY
  TSPDFLYVRSWLPCIFFAGGITMGNIGRQLAMYECKVIAEKSHQE
• Function: Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR. Acts as a negative regulator of cholesterol biosynthesis by mediating the retention of the SCAP-SREBP complex in the endoplasmic reticulum, thereby blocking the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2. Binds oxysterol, including 22-hydroxycholesterol, 24-hydroxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum. In presence of oxysterol, interacts with SCAP, retaining the SCAP-SREBP complex in the endoplasmic reticulum, thereby preventing SCAP from escorting SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi. Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding, disrupting the interaction between INSIG2 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2. Also regulates cholesterol synthesis by regulating degradation of HMGCR: initiates the sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligase RNF139.
• Reactome Pathway: Regulation of cholesterol biosynthesis by SREBP (SREBF) (R-HSA-1655829)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[1]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[1]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[2]
Cerebrovascular disease	DISAB237	Strong	Genetic Variation	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[5]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[6]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Biomarker	[7]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[5]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[8]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[5]
Peripheral vascular disease	DISXSU1Y	Strong	Genetic Variation	[2]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[9]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[10]
Split hand-foot malformation	DIS8PKGD	Strong	Genetic Variation	[11]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[12]
Coronary atherosclerosis	DISKNDYU	moderate	Genetic Variation	[13]
Asthma	DISW9QNS	Limited	Genetic Variation	[14]
Neoplasm	DISZKGEW	Limited	Altered Expression	[15]

3 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 Insulin-induced gene 2 protein (INSIG2).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Insulin-induced gene 2 protein (INSIG2).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Insulin-induced gene 2 protein (INSIG2).	[31]

22 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 Insulin-induced gene 2 protein (INSIG2).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Insulin-induced gene 2 protein (INSIG2).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Insulin-induced gene 2 protein (INSIG2).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Insulin-induced gene 2 protein (INSIG2).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Insulin-induced gene 2 protein (INSIG2).	[21]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Insulin-induced gene 2 protein (INSIG2).	[23]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Insulin-induced gene 2 protein (INSIG2).	[24]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Insulin-induced gene 2 protein (INSIG2).	[25]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Insulin-induced gene 2 protein (INSIG2).	[26]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Insulin-induced gene 2 protein (INSIG2).	[27]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Insulin-induced gene 2 protein (INSIG2).	[28]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Insulin-induced gene 2 protein (INSIG2).	[29]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Insulin-induced gene 2 protein (INSIG2).	[28]
Vandetanib	DMRICNP	Approved	Vandetanib increases the expression of Insulin-induced gene 2 protein (INSIG2).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Insulin-induced gene 2 protein (INSIG2).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Insulin-induced gene 2 protein (INSIG2).	[33]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Insulin-induced gene 2 protein (INSIG2).	[34]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Insulin-induced gene 2 protein (INSIG2).	[35]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Insulin-induced gene 2 protein (INSIG2).	[36]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Insulin-induced gene 2 protein (INSIG2).	[37]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Insulin-induced gene 2 protein (INSIG2).	[38]
Linalool	DMGZQ5P	Investigative	Linalool increases the expression of Insulin-induced gene 2 protein (INSIG2).	[39]

References

• [1] The INSIG2 rs7566605 genetic variant does not play a major role in obesity in a sample of 24,722 individuals from four cohorts.BMC Med Genet. 2009 Jun 12;10:56. doi: 10.1186/1471-2350-10-56.
• [2] Association of an INSIG2 obesity allele with cardiovascular phenotypes is gender and age dependent.BMC Cardiovasc Disord. 2010 Sep 29;10:46. doi: 10.1186/1471-2261-10-46.
• [3] Insulin-induced gene 2 expression correlates with colorectal cancer metastasis and disease outcome.IUBMB Life. 2016 Jan;68(1):65-71. doi: 10.1002/iub.1461. Epub 2015 Dec 10.
• [4] Insig2 is associated with colon tumorigenesis and inhibits Bax-mediated apoptosis.Int J Cancer. 2008 Jul 15;123(2):273-282. doi: 10.1002/ijc.23510.
• [5] Insig2 is overexpressed in pancreatic cancer and its expression is induced by hypoxia.Cancer Sci. 2011 Jun;102(6):1137-43. doi: 10.1111/j.1349-7006.2011.01936.x. Epub 2011 Apr 27.
• [6] Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations.J Med Genet. 2014 Aug;51(8):537-44. doi: 10.1136/jmedgenet-2014-102405. Epub 2014 Jul 1.
• [7] Single nucleotide polymorphisms in obesity-related genes and the risk of esophageal cancers.Cancer Epidemiol Biomarkers Prev. 2008 Apr;17(4):1007-12. doi: 10.1158/1055-9965.EPI-08-0023.
• [8] Association of INSIG2 rs9308762 with ALT level independent of BMI.J Pediatr Gastroenterol Nutr. 2014 Feb;58(2):155-9. doi: 10.1097/MPG.0b013e3182a87b71.
• [9] Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS).BMC Med Genet. 2010 Jan 21;11:12. doi: 10.1186/1471-2350-11-12.
• [10] Association study of polymorphisms in insulin induced gene 2 (INSIG2) with antipsychotic-induced weight gain in European and African-American schizophrenia patients.Hum Psychopharmacol. 2010 Apr;25(3):253-9. doi: 10.1002/hup.1111.
• [11] Characterization of two ectrodactyly-associated translocation breakpoints separated by 2.5 Mb on chromosome 2q14.1-q14.2.Eur J Hum Genet. 2009 Aug;17(8):1024-33. doi: 10.1038/ejhg.2009.2. Epub 2009 Feb 18.
• [12] Tumour biology of obesity-related cancers: understanding the molecular concept for better diagnosis and treatment.Tumour Biol. 2016 Nov;37(11):14363-14380. doi: 10.1007/s13277-016-5357-7. Epub 2016 Sep 14.
• [13] The INSIG1 gene, not the INSIG2 gene, associated with coronary heart disease: tagSNPs and haplotype-based association study. The Beijing Atherosclerosis Study.Thromb Haemost. 2008 Nov;100(5):886-92.
• [14] Gene-gene and gene-environmental interactions of childhood asthma: a multifactor dimension reduction approach.PLoS One. 2012;7(2):e30694. doi: 10.1371/journal.pone.0030694. Epub 2012 Feb 15.
• [15] Correlation between gene expression of IGF-1R pathway markers and cetuximab benefit in metastatic colorectal cancer.Clin Cancer Res. 2012 Feb 15;18(4):1156-66. doi: 10.1158/1078-0432.CCR-11-1135. Epub 2012 Jan 31.
• [16] 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.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [22] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [23] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [24] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [25] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [26] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [27] 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.
• [28] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [29] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [30] ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model. Int J Cancer. 2006 Jan 15;118(2):483-9. doi: 10.1002/ijc.21340.
• [31] 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.
• [32] 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.
• [33] Bisphenol A enhances adipogenic signaling pathways in human mesenchymal stem cells. Genes Environ. 2020 Mar 11;42:13. doi: 10.1186/s41021-020-00150-6. eCollection 2020.
• [34] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [35] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [36] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [37] 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.
• [38] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [39] Linalool is a PPARalpha ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res. 2014 Jun;55(6):1098-110.