Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVIGJ4T)

• DOT Name: E3 ubiquitin-protein ligase TRIM23 (TRIM23)
• Synonyms: EC 2.3.2.27; ADP-ribosylation factor domain-containing protein 1; GTP-binding protein ARD-1; RING finger protein 46; RING-type E3 ubiquitin transferase TRIM23; Tripartite motif-containing protein 23
• Gene Name: TRIM23
• Related Disease:
  Ablepharon macrostomia syndrome
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Prostate cancer
  Prostate carcinoma
  Lung adenocarcinoma
  Neoplasm
  Breast disorder
  Colitis
  Colorectal carcinoma
  Complex neurodevelopmental disorder
  Gastric cancer
  Stomach cancer
• UniProt ID: TRI23_HUMAN
• PDB ID: 5VZV; 5VZW
• EC Number: 2.3.2.27
• Pfam ID: PF00025 ; PF00643 ; PF13445
• Sequence:
  MATLVVNKLGAGVDSGRQGSRGTAVVKVLECGVCEDVFSLQGDKVPRLLLCGHTVCHDCL
  TRLPLHGRAIRCPFDRQVTDLGDSGVWGLKKNFALLELLERLQNGPIGQYGAAEESIGIS
  GESIIRCDEDEAHLASVYCTVCATHLCSECSQVTHSTKTLAKHRRVPLADKPHEKTMCSQ
  HQVHAIEFVCLEEGCQTSPLMCCVCKEYGKHQGHKHSVLEPEANQIRASILDMAHCIRTF
  TEEISDYSRKLVGIVQHIEGGEQIVEDGIGMAHTEHVPGTAENARSCIRAYFYDLHETLC
  RQEEMALSVVDAHVREKLIWLRQQQEDMTILLSEVSAACLHCEKTLQQDDCRVVLAKQEI
  TRLLETLQKQQQQFTEVADHIQLDASIPVTFTKDNRVHIGPKMEIRVVTLGLDGAGKTTI
  LFKLKQDEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVVD
  SSHRDRISEAHSELAKLLTEKELRDALLLIFANKQDVAGALSVEEITELLSLHKLCCGRS
  WYIQGCDARSGMGLYEGLDWLSRQLVAAGVLDVA
• Function: Acts as an E3 ubiquitin-protein ligase. Plays an essential role in autophagy activation during viral infection. Mechanistically, activates TANK-binding kinase 1/TBK1 by facilitating its dimerization and ability to phosphorylate the selective autophagy receptor SQSTM1. In order to achieve this function, TRIM23 mediates 'Lys-27'-linked auto-ubiquitination of its ADP-ribosylation factor (ARF) domain to induce its GTPase activity and its recruitment to autophagosomes ; (Microbial infection) Mediates TRAF6 auto-ubiquitination in the presence of human cytomegalovirus protein UL144, resulting in the virally controlled activation of NF-kappa-B stimulation at early times of HCMV infection.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ablepharon macrostomia syndrome	DIS1P3YX	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[2]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	moderate	Altered Expression	[7]
Breast disorder	DISJTGMA	Limited	Biomarker	[8]
Colitis	DISAF7DD	Limited	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[9]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[10]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[7]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[7]

11 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 E3 ubiquitin-protein ligase TRIM23 (TRIM23).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase TRIM23 (TRIM23).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase TRIM23 (TRIM23).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase TRIM23 (TRIM23).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of E3 ubiquitin-protein ligase TRIM23 (TRIM23).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase TRIM23 (TRIM23).	[16]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of E3 ubiquitin-protein ligase TRIM23 (TRIM23).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of E3 ubiquitin-protein ligase TRIM23 (TRIM23).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase TRIM23 (TRIM23).	[19]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of E3 ubiquitin-protein ligase TRIM23 (TRIM23).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of E3 ubiquitin-protein ligase TRIM23 (TRIM23).	[21]

References

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• [2] Diverse roles of arrest defective 1 in cancer development.Arch Pharm Res. 2019 Dec;42(12):1040-1051. doi: 10.1007/s12272-019-01195-0. Epub 2019 Dec 7.
• [3] ARD1 contributes to IKK-mediated breast cancer tumorigenesis.Cell Death Dis. 2018 Aug 28;9(9):860. doi: 10.1038/s41419-018-0921-2.
• [4] ARD1/NAA10 in hepatocellular carcinoma: pathways and clinical implications.Exp Mol Med. 2018 Jul 27;50(7):1-12. doi: 10.1038/s12276-018-0106-1.
• [5] ARD1/NAA10 acetylation in prostate cancer.Exp Mol Med. 2018 Jul 27;50(7):1-8. doi: 10.1038/s12276-018-0107-0.
• [6] Elevated TRIM23 expression predicts cisplatin resistance in lung adenocarcinoma.Cancer Sci. 2020 Feb;111(2):637-646. doi: 10.1111/cas.14226. Epub 2020 Jan 17.
• [7] Elevated TRIM23 expression predicts poor prognosis in Chinese gastric cancer.Pathol Res Pract. 2018 Dec;214(12):2062-2068. doi: 10.1016/j.prp.2018.10.010. Epub 2018 Oct 19.
• [8] Up-regulation of human arrest-defective 1 protein is correlated with metastatic phenotype and poor prognosis in breast cancer.Asian Pac J Cancer Prev. 2011;12(8):1973-7.
• [9] Generation of novel monoclonal antibodies and their application for detecting ARD1 expression in colorectal cancer.Cancer Lett. 2008 Jun 8;264(1):83-92. doi: 10.1016/j.canlet.2008.01.028. Epub 2008 Mar 5.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [13] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [14] 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.
• [15] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [18] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.