Details of Drug Off-Target (DOT)

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

• DOT Name: Interferon gamma receptor 2 (IFNGR2)
• Synonyms: IFN-gamma receptor 2; IFN-gamma-R2; Interferon gamma receptor accessory factor 1; AF-1; Interferon gamma receptor beta-chain; IFN-gamma-R-beta; Interferon gamma transducer 1
• Gene Name: IFNGR2
• Related Disease:
  Immunodeficiency 28
  Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency
  Autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency
  Autosomal recessive Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency
• UniProt ID: INGR2_HUMAN
• PDB ID: 5EH1; 6E3K; 6E3L
• Pfam ID: PF09294 ; PF01108
• Sequence:
  MRPTLLWSLLLLLGVFAAAAAAPPDPLSQLPAPQHPKIRLYNAEQVLSWEPVALSNSTRP
  VVYQVQFKYTDSKWFTADIMSIGVNCTQITATECDFTAASPSAGFPMDFNVTLRLRAELG
  ALHSAWVTMPWFQHYRNVTVGPPENIEVTPGEGSLIIRFSSPFDIADTSTAFFCYYVHYW
  EKGGIQQVKGPFRSNSISLDNLKPSRVYCLQVQAQLLWNKSNIFRVGHLSNISCYETMAD
  ASTELQQVILISVGTFSLLSVLAGACFFLVLKYRGLIKYWFHTPPSIPLQIEEYLKDPTQ
  PILEALDKDSSPKDDVWDSVSIISFPEKEQEDVLQTL
• Function: Associates with IFNGR1 to form a receptor for the cytokine interferon gamma (IFNG). Ligand binding stimulates activation of the JAK/STAT signaling pathway. Required for signal transduction in contrast to other receptor subunit responsible for ligand binding.
• Tissue Specificity: Expressed in T-cells (at protein level).
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  HIF-1 sig.ling pathway (hsa04066)
  Necroptosis (hsa04217)
  Osteoclast differentiation (hsa04380)
  JAK-STAT sig.ling pathway (hsa04630)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  Leishmaniasis (hsa05140)
  Chagas disease (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Influenza A (hsa05164)
  Herpes simplex virus 1 infection (hsa05168)
  Pathways in cancer (hsa05200)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Inflammatory bowel disease (hsa05321)
• Reactome Pathway:
  Regulation of IFNG signaling (R-HSA-877312)
  Potential therapeutics for SARS (R-HSA-9679191)
  IFNG signaling activates MAPKs (R-HSA-9732724)
  Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency 28	DIS5VBGX	Strong	Autosomal recessive	[1]
Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency	DISIHLZ8	Supportive	Autosomal dominant	[2]
Autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency	DISPHDQ6	Supportive	Autosomal recessive	[2]
Autosomal recessive Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency	DIS0E3QL	Supportive	Autosomal recessive	[2]

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 gamma receptor 2 (IFNGR2).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Interferon gamma receptor 2 (IFNGR2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Interferon gamma receptor 2 (IFNGR2).	[13]

13 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 gamma receptor 2 (IFNGR2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Interferon gamma receptor 2 (IFNGR2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interferon gamma receptor 2 (IFNGR2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Interferon gamma receptor 2 (IFNGR2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Interferon gamma receptor 2 (IFNGR2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Interferon gamma receptor 2 (IFNGR2).	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Interferon gamma receptor 2 (IFNGR2).	[11]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Interferon gamma receptor 2 (IFNGR2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Interferon gamma receptor 2 (IFNGR2).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Interferon gamma receptor 2 (IFNGR2).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Interferon gamma receptor 2 (IFNGR2).	[16]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Interferon gamma receptor 2 (IFNGR2).	[17]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Interferon gamma receptor 2 (IFNGR2).	[18]

References

• [1] Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease. Hum Mol Genet. 2013 Feb 15;22(4):769-81. doi: 10.1093/hmg/dds484. Epub 2012 Nov 16.
• [2] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [10] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [11] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [12] Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts. Biochem Biophys Res Commun. 2004 Feb 13;314(3):661-6. doi: 10.1016/j.bbrc.2003.12.146.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [17] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [18] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.