Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNOM26L)

• DOT Name: Tumor necrosis factor receptor superfamily member 9 (TNFRSF9)
• Synonyms: 4-1BB ligand receptor; CDw137; T-cell antigen 4-1BB homolog; T-cell antigen ILA; CD antigen CD137
• Gene Name: TNFRSF9
• Related Disease: Immunodeficiency 109 with lymphoproliferation
• UniProt ID: TNR9_HUMAN
• PDB ID: 6A3V; 6A3W; 6BWV; 6CPR; 6CU0; 6MGP; 6MHR; 6MI2; 6Y8K; 7D4B; 7YXU; 8GYE
• Pfam ID: PF00020
• Sequence:
  MGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQR
  TCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDC
  CFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAPARE
  PGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDG
  CSCRFPEEEEGGCEL
• Function: Receptor for TNFSF9/4-1BBL. Conveys a signal that enhances CD8(+) T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors (Probable).
• Tissue Specificity: Expressed on the surface of activated T-cells.
• 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
Immunodeficiency 109 with lymphoproliferation	DIS1N4WT	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[2]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[13]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[14]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[15]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[16]
HMPL-004	DM29XGY	Phase 3	HMPL-004 increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[17]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[17]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[21]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[22]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol increases the expression of Tumor necrosis factor receptor superfamily member 9 (TNFRSF9).	[17]

References

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• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Effect of chemical mutagens and carcinogens on gene expression profiles in human TK6 cells. PLoS One. 2012;7(6):e39205. doi: 10.1371/journal.pone.0039205. Epub 2012 Jun 18.
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• [15] 2,3,7,8-tetrachlorodibenzo-p-dioxin augments the modulation of gene expression mediated by the thyroid hormone receptor. Toxicol Appl Pharmacol. 2004 Feb 1;194(3):201-10. doi: 10.1016/j.taap.2003.09.010.
• [16] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [17] Mapping the dynamics of Nrf2 antioxidant and NFB inflammatory responses by soft electrophilic chemicals in human liver cells defines the transition from adaptive to adverse responses. Toxicol In Vitro. 2022 Oct;84:105419. doi: 10.1016/j.tiv.2022.105419. Epub 2022 Jun 17.
• [18] Benzo[a]pyrene promotes proliferation of human lung cancer cells by accelerating the epidermal growth factor receptor signaling pathway. Cancer Lett. 2009 Jun 8;278(1):27-33. doi: 10.1016/j.canlet.2008.12.017. Epub 2009 Jan 31.
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• [20] Genome-wide expression changes induced by bisphenol A, F and S in human stem cell derived hepatocyte-like cells. EXCLI J. 2020 Nov 4;19:1459-1476. doi: 10.17179/excli2020-2934. eCollection 2020.
• [21] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [22] Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. J Toxicol Environ Health A. 2008;71(22):1457-67. doi: 10.1080/15287390802329364.