Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOCBX7P)

• DOT Name: Tumor necrosis factor ligand superfamily member 4 (TNFSF4)
• Synonyms: Glycoprotein Gp34; OX40 ligand; OX40L; TAX transcriptionally-activated glycoprotein 1; CD antigen CD252
• Gene Name: TNFSF4
• UniProt ID: TNFL4_HUMAN
• PDB ID: 2HEV
• Sequence:
  MERVQPLEENVGNAARPRFERNKLLLVASVIQGLGLLLCFTYICLHFSALQVSHRYPRIQ
  SIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQEVNISLHYQ
  KDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELILIHQNPGEF
  CVL
• Function: Cytokine that binds to TNFRSF4. Co-stimulates T-cell proliferation and cytokine production.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)
• Reactome Pathway: TNFs bind their physiological receptors (R-HSA-5669034)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
D-myo-inositol 1,4,5-trisphosphate	DMNUKIX	Investigative	Tumor necrosis factor ligand superfamily member 4 (TNFSF4) increases the abundance of D-myo-inositol 1,4,5-trisphosphate.	[21]

22 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 Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[10]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[11]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[12]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Tumor necrosis factor ligand superfamily member 4 (TNFSF4).	[9]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] 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.
• [12] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Caffeine overcomes genistein-induced G2/M cell cycle arrest in breast cancer cells. Nutr Cancer. 2008;60(3):382-8.
• [16] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [20] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [21] OX40-OX40 ligand interaction may activate phospholipase C signal transduction pathway in human umbilical vein endothelial cells. Chem Biol Interact. 2009 Aug 14;180(3):460-4. doi: 10.1016/j.cbi.2009.04.009. Epub 2009 May 3.