Details of Drug Off-Target (DOT)

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

• DOT Name: TRAF family member-associated NF-kappa-B activator (TANK)
• Synonyms: TRAF-interacting protein; I-TRAF
• Gene Name: TANK
• Related Disease:
  Acute myelogenous leukaemia
  Intellectual disability
  Acute monocytic leukemia
  Advanced cancer
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Familial amyotrophic lateral sclerosis
  Hepatitis B virus infection
  Hypothyroidism
  Liver cirrhosis
  Liver failure
  Neoplasm
  Non-hodgkin lymphoma
  Obesity
  Psoriasis
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Astrocytoma
• UniProt ID: TANK_HUMAN
• PDB ID: 1KZZ; 1L0A; 5H10
• Pfam ID: PF12845
• Sequence:
  MDKNIGEQLNKAYEAFRQACMDRDSAVKELQQKTENYEQRIREQQEQLSLQQTIIDKLKS
  QLLLVNSTQDNNYGCVPLLEDSETRKNNLTLDQPQDKVISGIAREKLPKVRRQEVSSPRK
  ETSARSLGSPLLHERGNIEKTFWDLKEEFHKICMLAKAQKDHLSKLNIPDTATETQCSVP
  IQCTDKTDKQEALFKPQAKDDINRGAPSITSVTPRGLCRDEEDTSFESLSKFNVKFPPMD
  NDSTFLHSTPERPGILSPATSEAVCQEKFNMEFRDNPGNFVKTEETLFEIQGIDPIASAI
  QNLKTTDKTKPSNLVNTCIRTTLDRAACLPPGDHNALYVNSFPLLDPSDAPFPSLDSPGK
  AIRGPQQPIWKPFPNQDSDSVVLSGTDSELHIPRVCEFCQAVFPPSITSRGDFLRHLNSH
  FNGET
• Function: Adapter protein involved in I-kappa-B-kinase (IKK) regulation which constitutively binds TBK1 and IKBKE playing a role in antiviral innate immunity. Acts as a regulator of TRAF function by maintaining them in a latent state. Blocks TRAF2 binding to LMP1 and inhibits LMP1-mediated NF-kappa-B activation. Negatively regulates NF-kappaB signaling and cell survival upon DNA damage. Plays a role as an adapter to assemble ZC3H12A, USP10 in a deubiquitination complex which plays a negative feedback response to attenuate NF-kappaB activation through the deubiquitination of IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage. Promotes UBP10-induced deubiquitination of TRAF6 in response to DNA damage. May control negatively TRAF2-mediated NF-kappa-B activation signaled by CD40, TNFR1 and TNFR2.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  TRAF6 mediated IRF7 activation (R-HSA-933541)
  Activation of IRF3, IRF7 mediated by TBK1, IKK (IKBKE) (R-HSA-936964)
  TICAM1-dependent activation of IRF3/IRF7 (R-HSA-9013973)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Intellectual disability	DISMBNXP	Definitive	Biomarker	[2]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Genetic Variation	[9]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[10]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[11]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[10]
Liver failure	DISLGEL6	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[12]
Obesity	DIS47Y1K	Strong	Genetic Variation	[13]
Psoriasis	DIS59VMN	Strong	Biomarker	[14]
Inflammatory bowel disease	DISGN23E	moderate	Biomarker	[8]
Lung cancer	DISCM4YA	Disputed	Biomarker	[15]
Lung carcinoma	DISTR26C	Disputed	Biomarker	[15]
Astrocytoma	DISL3V18	Limited	Altered Expression	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of TRAF family member-associated NF-kappa-B activator (TANK).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of TRAF family member-associated NF-kappa-B activator (TANK).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of TRAF family member-associated NF-kappa-B activator (TANK).	[34]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of TRAF family member-associated NF-kappa-B activator (TANK).	[33]

20 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 TRAF family member-associated NF-kappa-B activator (TANK).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[20]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[21]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[23]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[25]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[20]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[26]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[27]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[25]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[28]
Imatinib	DM7RJXL	Approved	Imatinib increases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[29]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[30]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[31]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[32]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[26]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[35]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of TRAF family member-associated NF-kappa-B activator (TANK).	[23]

References

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• [11] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
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• [15] TIFA Promotes Cell Survival and Migration in Lung Adenocarcinoma.Cell Physiol Biochem. 2018;47(5):2097-2108. doi: 10.1159/000491478. Epub 2018 Jul 5.
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• [23] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [24] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
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• [29] Effects of Imatinib Mesylate (Gleevec) on human islet NF-kappaB activation and chemokine production in vitro. PLoS One. 2011;6(9):e24831. doi: 10.1371/journal.pone.0024831. Epub 2011 Sep 14.
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• [31] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [32] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [33] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
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• [35] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.