Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDK74C0)

• DOT Name: Tumor necrosis factor receptor superfamily member 4 (TNFRSF4)
• Synonyms: ACT35 antigen; OX40L receptor; TAX transcriptionally-activated glycoprotein 1 receptor; CD antigen CD134
• Gene Name: TNFRSF4
• Related Disease: Combined immunodeficiency due to OX40 deficiency
• UniProt ID: TNR4_HUMAN
• PDB ID: 1D0A; 2HEV; 2HEY; 6OGX; 6OKM; 6OKN; 7YK4; 8AG1
• Pfam ID: PF00020
• Sequence:
  MCVGARRLGRGPCAALLLLGLGLSTVTGLHCVGDTYPSNDRCCHECRPGNGMVSRCSRSQ
  NTVCRPCGPGFYNDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVCRCRAGTQPLDSYK
  PGVDCAPCPPGHFSPGDNQACKPWTNCTLAGKHTLQPASNSSDAICEDRDPPATQPQETQ
  GPPARPITVQPTEAWPRTSQGPSTRPVEVPGGRAVAAILGLGLVLGLLGPLAILLALYLL
  RRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI
• Function: Receptor for TNFSF4/OX40L/GP34. Is a costimulatory molecule implicated in long-term T-cell immunity; (Microbial infection) Acts as a receptor for human herpesvirus 6B/HHV-6B.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)
• Reactome Pathway: TNFs bind their physiological receptors (R-HSA-5669034)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Combined immunodeficiency due to OX40 deficiency	DISTZ04G	Supportive	Autosomal recessive	[1]

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 Tumor necrosis factor receptor superfamily member 4 (TNFRSF4).	[2]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Tumor necrosis factor receptor superfamily member 4 (TNFRSF4).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tumor necrosis factor receptor superfamily member 4 (TNFRSF4).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tumor necrosis factor receptor superfamily member 4 (TNFRSF4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tumor necrosis factor receptor superfamily member 4 (TNFRSF4).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tumor necrosis factor receptor superfamily member 4 (TNFRSF4).	[5]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Tumor necrosis factor receptor superfamily member 4 (TNFRSF4).	[7]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Tumor necrosis factor receptor superfamily member 4 (TNFRSF4).	[8]
Pimecrolimus	DMZLGRB	Approved	Pimecrolimus decreases the expression of Tumor necrosis factor receptor superfamily member 4 (TNFRSF4).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tumor necrosis factor receptor superfamily member 4 (TNFRSF4).	[11]

References

• [1] Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood. J Exp Med. 2013 Aug 26;210(9):1743-59. doi: 10.1084/jem.20130592. Epub 2013 Jul 29.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [6] 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.
• [7] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [8] Simvastatin reduces OX40 and OX40 ligand expression in human peripheral blood mononuclear cells and in patients with atherosclerotic cerebral infarction. J Int Med Res. 2009 May-Jun;37(3):601-10. doi: 10.1177/147323000903700302.
• [9] Pimecrolimus inhibits up-regulation of OX40 and synthesis of inflammatory cytokines upon secondary T cell activation by allogeneic dendritic cells. Clin Exp Immunol. 2002 Oct;130(1):85-92. doi: 10.1046/j.1365-2249.2002.01962.x.
• [10] 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.
• [11] 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.