Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI4EOAR)

• DOT Name: Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2)
• Synonyms: IFIT-2; ISG-54 K; Interferon-induced 54 kDa protein; IFI-54K; P54
• Gene Name: IFIT2
• Related Disease:
  Neuroblastoma
  Rabies
  Advanced cancer
  Aicardi-Goutieres syndrome
  Astrocytoma
  Candidiasis, invasive
  Gastric cancer
  Influenza
  Invasive candidiasis
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Non-small-cell lung cancer
  Osteoporosis
  Respiratory syncytial virus infection
  Squamous cell carcinoma
  Stomach cancer
  Triple negative breast cancer
  Colorectal carcinoma
  Melanoma
  Neoplasm
  Rheumatoid arthritis
• UniProt ID: IFIT2_HUMAN
• PDB ID: 4G1T
• Pfam ID: PF13181
• Sequence:
  MSENNKNSLESSLRQLKCHFTWNLMEGENSLDDFEDKVFYRTEFQNREFKATMCNLLAYL
  KHLKGQNEAALECLRKAEELIQQEHADQAEIRSLVTWGNYAWVYYHMGRLSDVQIYVDKV
  KHVCEKFSSPYRIESPELDCEEGWTRLKCGGNQNERAKVCFEKALEKKPKNPEFTSGLAI
  ASYRLDNWPPSQNAIDPLRQAIRLNPDNQYLKVLLALKLHKMREEGEEEGEGEKLVEEAL
  EKAPGVTDVLRSAAKFYRRKDEPDKAIELLKKALEYIPNNAYLHCQIGCCYRAKVFQVMN
  LRENGMYGKRKLLELIGHAVAHLKKADEANDNLFRVCSILASLHALADQYEDAEYYFQKE
  FSKELTPVAKQLLHLRYGNFQLYQMKCEDKAIHHFIEGVKINQKSREKEKMKDKLQKIAK
  MRLSKNGADSEALHVLAFLQELNEKMQQADEDSERGLESGSLIPSASSWNGE
• Function: IFN-induced antiviral protein which inhibits expression of viral messenger RNAs lacking 2'-O-methylation of the 5' cap. The ribose 2'-O-methylation would provide a molecular signature to distinguish between self and non-self mRNAs by the host during viral infection. Viruses evolved several ways to evade this restriction system such as encoding their own 2'-O-methylase for their mRNAs or by stealing host cap containing the 2'-O-methylation (cap snatching mechanism). Binds AU-rich viral RNAs, with or without 5' triphosphorylation, RNA-binding is required for antiviral activity. Can promote apoptosis.
• Reactome Pathway: Interferon alpha/beta signaling (R-HSA-909733)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[1]
Rabies	DISSC4V5	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Aicardi-Goutieres syndrome	DIS1NH4X	Strong	Altered Expression	[2]
Astrocytoma	DISL3V18	Strong	Altered Expression	[3]
Candidiasis, invasive	DIS5VDG3	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Influenza	DIS3PNU3	Strong	Biomarker	[5]
Invasive candidiasis	DIS5EI0L	Strong	Biomarker	[4]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung carcinoma	DISTR26C	Strong	Biomarker	[6]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Osteoporosis	DISF2JE0	Strong	Biomarker	[7]
Respiratory syncytial virus infection	DIS7FWHY	Strong	Biomarker	[8]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[9]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[2]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[10]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[11]
Melanoma	DIS1RRCY	moderate	Altered Expression	[12]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[2]
Rheumatoid arthritis	DISTSB4J	Disputed	Altered Expression	[13]

21 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 Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[22]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[23]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[24]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[25]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[26]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline decreases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[27]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[28]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[29]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[32]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[34]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2).	[33]

References

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• [2] Decreased IFIT2 Expression Promotes Gastric Cancer Progression and Predicts Poor Prognosis of the Patients.Cell Physiol Biochem. 2018;45(1):15-25. doi: 10.1159/000486219. Epub 2017 Dec 22.
• [3] ISG54 and ISG56 are induced by TLR3 signaling in U373MG human astrocytoma cells: possible involvement in CXCL10 expression.Neurosci Res. 2014 Jul;84:34-42. doi: 10.1016/j.neures.2014.03.001. Epub 2014 Mar 11.
• [4] Pathogenic Effects of IFIT2 and Interferon- during Fatal Systemic Candida albicans Infection.mBio. 2018 Apr 17;9(2):e00365-18. doi: 10.1128/mBio.00365-18.
• [5] A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2.PLoS One. 2013;8(1):e52198. doi: 10.1371/journal.pone.0052198. Epub 2013 Jan 9.
• [6] Decreased IFIT2 Expression In Human Non-Small-Cell Lung Cancer Tissues Is Associated With Cancer Progression And Poor Survival Of The Patients.Onco Targets Ther. 2019 Oct 3;12:8139-8149. doi: 10.2147/OTT.S220698. eCollection 2019.
• [7] Identification of novel genes associated with fracture healing in osteoporosis induced by Krm2 overexpression or Lrp5 deficiency.Mol Med Rep. 2017 Jun;15(6):3969-3976. doi: 10.3892/mmr.2017.6544. Epub 2017 May 3.
• [8] CDK9-dependent transcriptional elongation in the innate interferon-stimulated gene response to respiratory syncytial virus infection in airway epithelial cells.J Virol. 2013 Jun;87(12):7075-92. doi: 10.1128/JVI.03399-12. Epub 2013 Apr 17.
• [9] IFN-induced protein with tetratricopeptide repeats 2 inhibits migration activity and increases survival of oral squamous cell carcinoma.Mol Cancer Res. 2008 Sep;6(9):1431-9. doi: 10.1158/1541-7786.MCR-08-0141.
• [10] Baicalein Suppresses Stem Cell-Like Characteristics in Radio- and Chemoresistant MDA-MB-231 Human Breast Cancer Cells through Up-Regulation of IFIT2.Nutrients. 2019 Mar 14;11(3):624. doi: 10.3390/nu11030624.
• [11] Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/-catenin signaling in colorectal cancer cells.Oncogene. 2019 Aug;38(32):6051-6064. doi: 10.1038/s41388-019-0856-9. Epub 2019 Jul 10.
• [12] Modulation of SOCS protein expression influences the interferon responsiveness of human melanoma cells.BMC Cancer. 2010 Apr 14;10:142. doi: 10.1186/1471-2407-10-142.
• [13] P54/nrb prompts rheumatoid arthritis progression mainly by transcriptionally activating NF-B signaling.Pharmazie. 2017 May 1;72(5):260-264. doi: 10.1691/ph.2017.6904.
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• [16] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [17] 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.
• [18] 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.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [21] 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.
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• [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] 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.
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• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [30] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [31] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [32] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [33] 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.
• [34] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [35] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.