Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7AU2R3)

• DOT Name: TRAF-type zinc finger domain-containing protein 1 (TRAFD1)
• Synonyms: Protein FLN29
• Gene Name: TRAFD1
• Related Disease: Esophageal cancer
• UniProt ID: TRAD1_HUMAN
• PDB ID: 2D9K
• Pfam ID: PF21366
• Sequence:
  MAEFLDDQETRLCDNCKKEIPVFNFTIHEIHCQRNIGMCPTCKEPFPKSDMETHMAAEHC
  QVTCKCNKKLEKRLLKKHEETECPLRLAVCQHCDLELSILKLKEHEDYCGARTELCGNCG
  RNVLVKDLKTHPEVCGREGEEKRNEVAIPPNAYDESWGQDGIWIASQLLRQIEALDPPMR
  LPRRPLRAFESDVFHNRTTNQRNITAQVSIQNNLFEEQERQERNRGQQPPKEGGEESANL
  DFMLALSLQNEGQASSVAEQDFWRAVCEADQSHGGPRSLSDIKGAADEIMLPCEFCEELY
  PEELLIDHQTSCNPSRALPSLNTGSSSPRGVEEPDVIFQNFLQQAASNQLDSLMGLSNSH
  PVEESIIIPCEFCGVQLEEEVLFHHQDQCDQRPATATNHVTEGIPRLDSQPQETSPELPR
  RRVRHQGDLSSGYLDDTKQETANGPTSCLPPSRPINNMTATYNQLSRSTSGPRPGCQPSS
  PCVPKLSNSDSQDIQGRNRDSQNGAIAPGHVSVIRPPQNLYPENIVPSFSPGPSGRYGAS
  GRSEGGRNSRVTPAAANYRSRTAKAKPSKQQGAGDAEEEEEE
• Function: Negative feedback regulator that controls excessive innate immune responses. Regulates both Toll-like receptor 4 (TLR4) and DDX58/RIG1-like helicases (RLH) pathways. May inhibit the LTR pathway by direct interaction with TRAF6 and attenuation of NF-kappa-B activation. May negatively regulate the RLH pathway downstream from MAVS and upstream of NF-kappa-B and IRF3.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[1]

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-type zinc finger domain-containing protein 1 (TRAFD1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[11]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[5]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[5]
Clodronate	DM9Y6X7	Approved	Clodronate affects the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[5]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil decreases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of TRAF-type zinc finger domain-containing protein 1 (TRAFD1).	[14]

References

• [1] Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations.Nat Genet. 2011 Jun 5;43(7):679-84. doi: 10.1038/ng.849.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.