Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0V1YVC)

• DOT Name: Tripartite motif-containing protein 2 (TRIM2)
• Synonyms: EC 2.3.2.27; E3 ubiquitin-protein ligase TRIM2; RING finger protein 86; RING-type E3 ubiquitin transferase TRIM2
• Gene Name: TRIM2
• Related Disease:
  Epithelial ovarian cancer
  Charcot marie tooth disease
  Colorectal carcinoma
  Dementia
  Metastatic malignant neoplasm
  Osteoarthritis
  Peripheral neuropathy
  Viral hemorrhagic fever
  Clear cell renal carcinoma
  Charcot-Marie-Tooth disease type 2R
  Bone osteosarcoma
  Neoplasm
  Osteosarcoma
• UniProt ID: TRIM2_HUMAN
• PDB ID: 7B2R; 7B96; 7QRV; 7ZJ3; 8A38; 8AMS
• EC Number: 2.3.2.27
• Pfam ID: PF00630 ; PF01436 ; PF00643 ; PF13445
• Sequence:
  MASEGTNIPSPVVRQIDKQFLICSICLERYKNPKVLPCLHTFCERCLQNYIPAHSLTLSC
  PVCRQTSILPEKGVAALQNNFFITNLMDVLQRTPGSNAEESSILETVTAVAAGKPLSCPN
  HDGNVMEFYCQSCETAMCRECTEGEHAEHPTVPLKDVVEQHKASLQVQLDAVNKRLPEID
  SALQFISEIIHQLTNQKASIVDDIHSTFDELQKTLNVRKSVLLMELEVNYGLKHKVLQSQ
  LDTLLQGQESIKSCSNFTAQALNHGTETEVLLVKKQMSEKLNELADQDFPLHPRENDQLD
  FIVETEGLKKSIHNLGTILTTNAVASETVATGEGLRQTIIGQPMSVTITTKDKDGELCKT
  GNAYLTAELSTPDGSVADGEILDNKNGTYEFLYTVQKEGDFTLSLRLYDQHIRGSPFKLK
  VIRSADVSPTTEGVKRRVKSPGSGHVKQKAVKRPASMYSTGKRKENPIEDDLIFRVGTKG
  RNKGEFTNLQGVAASTNGKILIADSNNQCVQIFSNDGQFKSRFGIRGRSPGQLQRPTGVA
  VHPSGDIIIADYDNKWVSIFSSDGKFKTKIGSGKLMGPKGVSVDRNGHIIVVDNKACCVF
  IFQPNGKIVTRFGSRGNGDRQFAGPHFAAVNSNNEIIITDFHNHSVKVFNQEGEFMLKFG
  SNGEGNGQFNAPTGVAVDSNGNIIVADWGNSRIQVFDGSGSFLSYINTSADPLYGPQGLA
  LTSDGHVVVADSGNHCFKVYRYLQ
• Function: UBE2D1-dependent E3 ubiquitin-protein ligase that mediates the ubiquitination of NEFL and of phosphorylated BCL2L11. Plays a neuroprotective function. May play a role in neuronal rapid ischemic tolerance. Plays a role in antiviral immunity and limits New World arenavirus infection independently of its ubiquitin ligase activity.
• Reactome Pathway: Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Definitive	Biomarker	[1]
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Dementia	DISXL1WY	Strong	Biomarker	[4]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[3]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[5]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[6]
Viral hemorrhagic fever	DISQEBTU	Strong	Biomarker	[2]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[7]
Charcot-Marie-Tooth disease type 2R	DISQFY67	Supportive	Autosomal recessive	[8]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[9]
Neoplasm	DISZKGEW	Limited	Biomarker	[3]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[9]

This DOT Affected the Drug Response of 8 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Tripartite motif-containing protein 2 (TRIM2) affects the response to substance of Doxorubicin.	[26]
Fluorouracil	DMUM7HZ	Approved	Tripartite motif-containing protein 2 (TRIM2) affects the response to substance of Fluorouracil.	[26]
Etoposide	DMNH3PG	Approved	Tripartite motif-containing protein 2 (TRIM2) affects the response to substance of Etoposide.	[26]
Paclitaxel	DMLB81S	Approved	Tripartite motif-containing protein 2 (TRIM2) affects the response to substance of Paclitaxel.	[26]
Mitomycin	DMH0ZJE	Approved	Tripartite motif-containing protein 2 (TRIM2) affects the response to substance of Mitomycin.	[26]
Topotecan	DMP6G8T	Approved	Tripartite motif-containing protein 2 (TRIM2) affects the response to substance of Topotecan.	[26]
Mitoxantrone	DMM39BF	Approved	Tripartite motif-containing protein 2 (TRIM2) affects the response to substance of Mitoxantrone.	[26]
Vinblastine	DM5TVS3	Approved	Tripartite motif-containing protein 2 (TRIM2) affects the response to substance of Vinblastine.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tripartite motif-containing protein 2 (TRIM2).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tripartite motif-containing protein 2 (TRIM2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tripartite motif-containing protein 2 (TRIM2).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tripartite motif-containing protein 2 (TRIM2).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Tripartite motif-containing protein 2 (TRIM2).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Tripartite motif-containing protein 2 (TRIM2).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Tripartite motif-containing protein 2 (TRIM2).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Tripartite motif-containing protein 2 (TRIM2).	[15]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Tripartite motif-containing protein 2 (TRIM2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tripartite motif-containing protein 2 (TRIM2).	[20]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Tripartite motif-containing protein 2 (TRIM2).	[22]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Tripartite motif-containing protein 2 (TRIM2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Tripartite motif-containing protein 2 (TRIM2).	[24]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Tripartite motif-containing protein 2 (TRIM2).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Tripartite motif-containing protein 2 (TRIM2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tripartite motif-containing protein 2 (TRIM2).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tripartite motif-containing protein 2 (TRIM2).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Tripartite motif-containing protein 2 (TRIM2).	[21]

References

• [1] MicroRNA-145 targets TRIM2 and exerts tumor-suppressing functions in epithelial ovarian cancer.Gynecol Oncol. 2015 Dec;139(3):513-9. doi: 10.1016/j.ygyno.2015.10.008. Epub 2015 Oct 16.
• [2] TRIM2, a novel member of the antiviral family, limits New World arenavirus entry.PLoS Biol. 2019 Feb 6;17(2):e3000137. doi: 10.1371/journal.pbio.3000137. eCollection 2019 Feb.
• [3] TRIM2 is a novel promoter of human colorectal cancer.Scand J Gastroenterol. 2019 Feb;54(2):210-218. doi: 10.1080/00365521.2019.1575463. Epub 2019 Mar 27.
• [4] MicroRNA-181c Ameliorates Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats.Mol Neurobiol. 2017 Dec;54(10):8370-8385. doi: 10.1007/s12035-016-0268-6. Epub 2016 Dec 8.
• [5] Distinctive gene expression signatures in rheumatoid arthritis synovial tissue fibroblast cells: correlates with disease activity.Genes Immun. 2007 Sep;8(6):480-91. doi: 10.1038/sj.gene.6364400. Epub 2007 Jun 14.
• [6] Exome sequencing reveals homozygous TRIM2 mutation in a patient with early onset CMT and bilateral vocal cord paralysis.Hum Genet. 2015 Jun;134(6):671-3. doi: 10.1007/s00439-015-1548-3. Epub 2015 Apr 17.
• [7] TRIM2 downregulation in clear cell renal cell carcinoma affects cell proliferation, migration, and invasion and predicts poor patients' survival.Cancer Manag Res. 2018 Nov 20;10:5951-5964. doi: 10.2147/CMAR.S185270. eCollection 2018.
• [8] Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy. Hum Mol Genet. 2013 Aug 1;22(15):2975-83. doi: 10.1093/hmg/ddt149. Epub 2013 Apr 4.
• [9] TRIM2 regulates the development and metastasis of tumorous cells of osteosarcoma.Int J Oncol. 2018 Oct;53(4):1643-1656. doi: 10.3892/ijo.2018.4494. Epub 2018 Jul 20.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [23] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [24] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [25] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.
• [26] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.