Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2QP8D3)

• DOT Name: Interferon-induced transmembrane protein 3 (IFITM3)
• Synonyms: Dispanin subfamily A member 2b; DSPA2b; Interferon-inducible protein 1-8U
• Gene Name: IFITM3
• Related Disease:
  Acute myelogenous leukaemia
  Adenoma
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Colitis
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Esophageal squamous cell carcinoma
  Glioma
  Hepatocellular carcinoma
  HIV infectious disease
  Immunodeficiency
  Influenza
  Liver cirrhosis
  Lung adenocarcinoma
  Melanoma
  Pancreatitis
  Salmonella infection
  Schizophrenia
  Ulcerative colitis
  Dengue
  Metastatic malignant neoplasm
  Colorectal carcinoma
  Tuberculosis
  Ebola virus infection
  Gastric cancer
  Middle East Respiratory Syndrome (MERS)
  Stomach cancer
  Zika virus infection
• UniProt ID: IFM3_HUMAN
• Pfam ID: PF04505
• Sequence:
  MNHTVQTFFSPVNSGQPPNYEMLKEEHEVAVLGAPHNPAPPTSTVIHIRSETSVPDHVVW
  SLFNTLFMNPCCLGFIAFAYSVKSRDRKMVGDVTGAQAYASTAKCLNIWALILGILMTIL
  LIVIPVLIFQAYG
• Function: IFN-induced antiviral protein which disrupts intracellular cholesterol homeostasis. Inhibits the entry of viruses to the host cell cytoplasm by preventing viral fusion with cholesterol depleted endosomes. May inactivate new enveloped viruses which buds out of the infected cell, by letting them go out with a cholesterol depleted membrane. Active against multiple viruses, including influenza A virus, SARS coronaviruses (SARS-CoV and SARS-CoV-2), Marburg virus (MARV), Ebola virus (EBOV), Dengue virus (DNV), West Nile virus (WNV), human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV) and vesicular stomatitis virus (VSV). Can inhibit: influenza virus hemagglutinin protein-mediated viral entry, MARV and EBOV GP1,2-mediated viral entry, SARS-CoV and SARS-CoV-2 S protein-mediated viral entry and VSV G protein-mediated viral entry. Plays a critical role in the structural stability and function of vacuolar ATPase (v-ATPase). Establishes physical contact with the v-ATPase of endosomes which is critical for proper clathrin localization and is also required for the function of the v-ATPase to lower the pH in phagocytic endosomes thus establishing an antiviral state. In hepatocytes, IFITM proteins act in a coordinated manner to restrict HCV infection by targeting the endocytosed HCV virion for lysosomal degradation. IFITM2 and IFITM3 display anti-HCV activity that may complement the anti-HCV activity of IFITM1 by inhibiting the late stages of HCV entry, possibly in a coordinated manner by trapping the virion in the endosomal pathway and targeting it for degradation at the lysosome. Exerts opposing activities on SARS-CoV-2, including amphipathicity-dependent restriction of virus at endosomes and amphipathicity-independent enhancement of infection at the plasma membrane.
• Reactome Pathway: Interferon alpha/beta signaling (R-HSA-909733)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Colitis	DISAF7DD	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[7]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[9]
HIV infectious disease	DISO97HC	Strong	Genetic Variation	[10]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[11]
Influenza	DIS3PNU3	Strong	Altered Expression	[12]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[9]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[13]
Melanoma	DIS1RRCY	Strong	Posttranslational Modification	[14]
Pancreatitis	DIS0IJEF	Strong	Altered Expression	[15]
Salmonella infection	DISTJ434	Strong	Biomarker	[15]
Schizophrenia	DISSRV2N	Strong	Biomarker	[16]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[5]
Dengue	DISKH221	moderate	Genetic Variation	[12]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[17]
Colorectal carcinoma	DIS5PYL0	Disputed	Altered Expression	[7]
Tuberculosis	DIS2YIMD	Disputed	Genetic Variation	[18]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[19]
Gastric cancer	DISXGOUK	Limited	Biomarker	[5]
Middle East Respiratory Syndrome (MERS)	DIS5VPYU	Limited	Genetic Variation	[20]
Stomach cancer	DISKIJSX	Limited	Biomarker	[5]
Zika virus infection	DISQUCTY	Limited	Biomarker	[19]

1 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-induced transmembrane protein 3 (IFITM3).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[25]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[26]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[27]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[28]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[29]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[30]
Selenium	DM25CGV	Approved	Selenium increases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[31]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[32]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[34]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[35]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[36]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[38]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[39]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[40]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[41]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Interferon-induced transmembrane protein 3 (IFITM3).	[42]

References

• [1] High IFITM3 expression predicts adverse prognosis in acute myeloid leukemia.Cancer Gene Ther. 2020 Feb;27(1-2):38-44. doi: 10.1038/s41417-019-0093-y. Epub 2019 Mar 29.
• [2] Gene-expression profiling in Chinese patients with colon cancer by coupling experimental and bioinformatic genomewide gene-expression analyses: identification and validation of IFITM3 as a biomarker of early colon carcinogenesis.Cancer. 2008 Jul 15;113(2):266-75. doi: 10.1002/cncr.23551.
• [3] Overexpression of IFITM3 predicts poor prognosis in stage IIA esophageal squamous cell carcinoma after Ivor Lewis esophagectomy.Thorac Cancer. 2017 Nov;8(6):592-599. doi: 10.1111/1759-7714.12488. Epub 2017 Aug 30.
• [4] Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease.Eur J Med Chem. 2017 Jan 5;125:736-750. doi: 10.1016/j.ejmech.2016.09.057. Epub 2016 Sep 19.
• [5] Mechanism and biological significance of the overexpression of IFITM3 in gastric cancer.Oncol Rep. 2014 Dec;32(6):2648-56. doi: 10.3892/or.2014.3522. Epub 2014 Oct 1.
• [6] The anti-inflammatory IFITM genes ameliorate colitis and partially protect from tumorigenesis by changing immunity and microbiota.Immunol Cell Biol. 2018 Mar;96(3):284-297. doi: 10.1111/imcb.12000. Epub 2018 Jan 22.
• [7] KLF4-mediated negative regulation of IFITM3 expression plays a critical role in colon cancer pathogenesis.Clin Cancer Res. 2011 Jun 1;17(11):3558-68. doi: 10.1158/1078-0432.CCR-10-2729. Epub 2011 Apr 29.
• [8] IFITM3/STAT3 axis promotes glioma cells invasion and is modulated by TGF-.Mol Biol Rep. 2020 Jan;47(1):433-441. doi: 10.1007/s11033-019-05146-2. Epub 2019 Oct 21.
• [9] Interferon-induced transmembrane protein-3 rs12252-CC is associated with low differentiation and progression of hepatocellular carcinoma.Medicine (Baltimore). 2019 Jan;98(2):e13996. doi: 10.1097/MD.0000000000013996.
• [10] Rhesus macaque IFITM3 gene polymorphisms and SIV infection.PLoS One. 2017 Mar 3;12(3):e0172847. doi: 10.1371/journal.pone.0172847. eCollection 2017.
• [11] Role of rhesus macaque IFITM3(2) in simian immunodeficiency virus infection of macaques.PLoS One. 2019 Nov 4;14(11):e0224082. doi: 10.1371/journal.pone.0224082. eCollection 2019.
• [12] Human megakaryocytes possess intrinsic antiviral immunity through regulated induction of IFITM3.Blood. 2019 May 9;133(19):2013-2026. doi: 10.1182/blood-2018-09-873984. Epub 2019 Feb 5.
• [13] Interferon induced transmembrane protein 3 regulates the growth and invasion of human lung adenocarcinoma.Thorac Cancer. 2017 Jul;8(4):337-343. doi: 10.1111/1759-7714.12451. Epub 2017 May 23.
• [14] Interferon-alpha induces reversible DNA demethylation of the interferon-induced transmembrane protein-3 core promoter in human melanoma cells.J Interferon Cytokine Res. 2011 Aug;31(8):601-8. doi: 10.1089/jir.2010.0134. Epub 2011 Mar 17.
• [15] Cloning of IP15, a pancreatitis-induced gene whose expression inhibits cell growth.Biochem Biophys Res Commun. 2004 Jul 2;319(3):1001-9. doi: 10.1016/j.bbrc.2004.05.085.
• [16] Immune system disturbances in schizophrenia.Biol Psychiatry. 2014 Feb 15;75(4):316-23. doi: 10.1016/j.biopsych.2013.06.010. Epub 2013 Jul 25.
• [17] IFITM3 promotes hepatocellular carcinoma invasion and metastasis by regulating MMP9 through p38/MAPK signaling.FEBS Open Bio. 2018 Jun 28;8(8):1299-1311. doi: 10.1002/2211-5463.12479. eCollection 2018 Aug.
• [18] A functional promoter polymorphism of IFITM3 is associated with susceptibility to pediatric tuberculosis in Han Chinese population.PLoS One. 2013 Jul 9;8(7):e67816. doi: 10.1371/journal.pone.0067816. Print 2013.
• [19] Chemical Synthesis of the Highly Hydrophobic Antiviral Membrane-Associated Protein IFITM3 and Modified Variants.Angew Chem Int Ed Engl. 2017 Oct 2;56(41):12639-12643. doi: 10.1002/anie.201707554. Epub 2017 Sep 7.
• [20] Identification of Residues Controlling Restriction versus Enhancing Activities of IFITM Proteins on Entry of Human Coronaviruses.J Virol. 2018 Feb 26;92(6):e01535-17. doi: 10.1128/JVI.01535-17. Print 2018 Mar 15.
• [21] 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.
• [22] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [23] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] 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.
• [26] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [27] 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.
• [28] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [29] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [30] The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009 Feb;41(2):178-186.
• [31] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [32] 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.
• [33] Impact of extracellular folate levels on global gene expression. Mol Pharmacol. 2001 Dec;60(6):1288-95. doi: 10.1124/mol.60.6.1288.
• [34] 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.
• [35] Integrated transcriptomic and metabolomic analyses to characterize the anti-cancer effects of (-)-epigallocatechin-3-gallate in human colon cancer cells. Toxicol Appl Pharmacol. 2020 Aug 15;401:115100. doi: 10.1016/j.taap.2020.115100. Epub 2020 Jun 6.
• [36] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [37] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [38] 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.
• [39] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [40] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [41] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [42] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.