Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXA2IXF)

• DOT Name: E3 ubiquitin-protein ligase TRIM50 (TRIM50)
• Synonyms: EC 2.3.2.27; RING-type E3 ubiquitin transferase TRIM50; Tripartite motif-containing protein 50
• Gene Name: TRIM50
• Related Disease:
  Epithelial ovarian cancer
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Hepatocellular carcinoma
• UniProt ID: TRI50_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13765 ; PF00622 ; PF00643 ; PF13445
• Sequence:
  MAWQVSLPELEDRLQCPICLEVFKEPLMLQCGHSYCKGCLVSLSCHLDAELRCPVCRQAV
  DGSSSLPNVSLARVIEALRLPGDPEPKVCVHHRNPLSLFCEKDQELICGLCGLLGSHQHH
  PVTPVSTVYSRMKEELAALISELKQEQKKVDELIAKLVNNRTRIVNESDVFSWVIRREFQ
  ELHHLVDEEKARCLEGIGGHTRGLVASLDMQLEQAQGTRERLAQAECVLEQFGNEDHHKF
  IRKFHSMASRAEMPQARPLEGAFSPISFKPGLHQADIKLTVWKRLFRKVLPAPEPLKLDP
  ATAHPLLELSKGNTVVQCGLLAQRRASQPERFDYSTCVLASRGFSCGRHYWEVVVGSKSD
  WRLGVIKGTASRKGKLNRSPEHGVWLIGLKEGRVYEAFACPRVPLPVAGHPHRIGLYLHY
  EQGELTFFDADRPDDLRPLYTFQADFQGKLYPILDTCWHERGSNSLPMVLPPPSGPGPLS
  PEQPTKL
• Function: E3 ubiquitin-protein ligase that ubiquitinates Beclin-1/BECN1 in a 'Lys-63'-dependent manner enhancing its binding to ULK1. In turn, promotes starvation-induced autophagy activation. Interacts also with p62/SQSTM1 protein and thereby induces the formation and the autophagy clearance of aggresome-associated polyubiquitinated proteins through HDAC6 interaction. Promotes also NLRP3 inflammasome activation by directly inducing NLRP3 oligomerization independent of its E3 ligase function.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[1]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	E3 ubiquitin-protein ligase TRIM50 (TRIM50) affects the response to substance of Temozolomide.	[8]
DTI-015	DMXZRW0	Approved	E3 ubiquitin-protein ligase TRIM50 (TRIM50) affects the response to substance of DTI-015.	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of E3 ubiquitin-protein ligase TRIM50 (TRIM50).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase TRIM50 (TRIM50).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase TRIM50 (TRIM50).	[4]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of E3 ubiquitin-protein ligase TRIM50 (TRIM50).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of E3 ubiquitin-protein ligase TRIM50 (TRIM50).	[5]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of E3 ubiquitin-protein ligase TRIM50 (TRIM50).	[5]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of E3 ubiquitin-protein ligase TRIM50 (TRIM50).	[7]

References

• [1] TRIM50 acts as a novel Src suppressor and inhibits ovarian cancer progression.Biochim Biophys Acta Mol Cell Res. 2019 Sep;1866(9):1412-1420. doi: 10.1016/j.bbamcr.2019.06.002. Epub 2019 Jun 6.
• [2] TRIM50 suppressed hepatocarcinoma progression through directly targeting SNAIL for ubiquitous degradation.Cell Death Dis. 2018 May 22;9(6):608. doi: 10.1038/s41419-018-0644-4.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [6] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [7] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [8] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.