Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0VJCP6)

• DOT Name: Tripartite motif-containing protein 66 (TRIM66)
• Gene Name: TRIM66
• Related Disease:
  Lung cancer
  Lung carcinoma
  Bone osteosarcoma
  Colorectal carcinoma
  Holt-Oram syndrome
  Obesity
  Osteosarcoma
  Hepatocellular carcinoma
  Non-small-cell lung cancer
• UniProt ID: TRI66_HUMAN
• PDB ID: 6IET; 6IEU
• Pfam ID: PF00439 ; PF00628 ; PF00643
• Sequence:
  MSFMGLPLAGQKHCPKSGQMEAMVMTCSLCHQDLPGMGSHLLSCQHLLRKDCFQGLIQEL
  GQIAKAHETVADELISCPGCERVYLTRDVTEHFFLHCVPTEQPKMARNCSECKEKRAAHI
  LCTYCNRWLCSSCTEEHRHSPVPGGPFFPRAQKGSPGVNGGPGDFTLYCPLHTQEVLKLF
  CETCDMLTCHSCLVVEHKEHRCRHVEEVLQNQRMLLEGVTTQVAHKKSSLQTSAKQIEDR
  IFEVKHQHRKVENQIKMAKMVLMNELNKQANGLIEELEGITNERKRKLEQQLQSIMVLNR
  QFEHVQNFINWAVCSKTSVPFLFSKELIVFQMQRLLETSCNTDPGSPWSIRFTWEPNFWT
  KQLASLGCITTEGGQMSRADAPAYGGLQGSSPFYQSHQSPVAQQEALSHPSHKFQSPAVC
  SSSVCCSHCSPVSPSLKGQVPPPSIHPAHSFRQPPEMVPQQLGSLQCSALLPREKELACS
  PHPPKLLQPWLETQPPVEQESTSQRLGQQLTSQPVCIVPPQDVQQGAHAQPTLQTPSIQV
  QFGHHQKLKLSHFQQQPQQQLPPPPPPLPHPPPPLPPPPQQPHPPLPPSQHLASSQHESP
  PGPACSQNMDIMHHKFELEEMQKDLELLLQAQQPSLQLSQTKSPQHLQQTIVGQINYIVR
  QPAPVQSQSQEETLQATDEPPASQGSKPALPLDKNTAAALPQASGEETPLSVPPVDSTIQ
  HSSPNVVRKHSTSLSIMGFSNTLEMELSSTRLERPLEPQIQSVSNLTAGAPQAVPSLLSA
  PPKMVSSLTSVQNQAMPSLTTSHLQTVPSLVHSTFQSMPNLISDSPQAMASLASDHPQAG
  PSLMSGHTQAVPSLATCPLQSIPPVSDMQPETGSSSSSGRTSGSLCPRDGADPSLENALC
  KMESEDSTRFTDLLGQGPIVPGLDAPKDLAIPSELEEPINLSVKKPPLAPVVSTSTALQQ
  YQNPKECENFEQGALELDAKENQSIRAFNSEHKIPYVRLERLKICAASSGEMPVFKLKPQ
  KNDQDGSFLLIIECGTESSSMSIKVSQDRLSEATQAPGLEGRKVTVTSLAGQRPPEVEGT
  SPEEHRLIPRTPGAKKGPPAPIENEDFCAVCLNGGELLCCDRCPKVFHLSCHVPALLSFP
  GGEWVCTLCRSLTQPEMEYDCENACYNQPGMRASPGLSMYDQKKCEKLVLSLCCNNLSLP
  FHEPVSPLARHYYQIIKRPMDLSIIRRKLQKKDPAHYTTPEEVVSDVRLMFWNCAKFNYP
  DSEVAEAGRCLEVFFEGWLKEIYPEKRFAQPRQEDSDSEEVSSESGCSTPQGFPWPPYMQ
  EGIQPKRRRRHMENERAKRMSFRLANSISQV
• Function: May function as transcription repressor; The repressive effects are mediated, at least in part, by recruitment of deacetylase activity. May play a role as negative regulator of postmeiotic genes acting through CBX3 complex formation and centromere association.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Holt-Oram syndrome	DISBNDZ2	Strong	Biomarker	[4]
Obesity	DIS47Y1K	Strong	Genetic Variation	[5]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[7]

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 Tripartite motif-containing protein 66 (TRIM66).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tripartite motif-containing protein 66 (TRIM66).	[12]

6 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 Tripartite motif-containing protein 66 (TRIM66).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tripartite motif-containing protein 66 (TRIM66).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tripartite motif-containing protein 66 (TRIM66).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Tripartite motif-containing protein 66 (TRIM66).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Tripartite motif-containing protein 66 (TRIM66).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Tripartite motif-containing protein 66 (TRIM66).	[15]

References

• [1] Knockdown of TRIM66 inhibits malignant behavior and epithelial-mesenchymal transition in non-small cell lung cancer.Pathol Res Pract. 2018 Aug;214(8):1130-1135. doi: 10.1016/j.prp.2018.06.008. Epub 2018 Jun 18.
• [2] miR-451a Inhibits the Growth and Invasion of Osteosarcoma via Targeting TRIM66.Technol Cancer Res Treat. 2019 Jan 1;18:1533033819870209. doi: 10.1177/1533033819870209.
• [3] Knockdown of TRIM66 inhibits cell proliferation, migration and invasion in colorectal cancer through JAK2/STAT3 pathway.Life Sci. 2019 Oct 15;235:116799. doi: 10.1016/j.lfs.2019.116799. Epub 2019 Aug 28.
• [4] TRIM66 overexpresssion contributes to osteosarcoma carcinogenesis and indicates poor survival outcome.Oncotarget. 2015 Sep 15;6(27):23708-19. doi: 10.18632/oncotarget.4291.
• [5] Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.Nat Genet. 2013 May;45(5):501-12. doi: 10.1038/ng.2606. Epub 2013 Apr 7.
• [6] TRIM66 confers tumorigenicity of hepatocellular carcinoma cells by regulating GSK-3-dependent Wnt/-catenin signaling.Eur J Pharmacol. 2019 May 5;850:109-117. doi: 10.1016/j.ejphar.2019.01.054. Epub 2019 Jan 30.
• [7] LncRNA TATDN1 contributes to the cisplatin resistance of non-small cell lung cancer through TATDN1/miR-451/TRIM66 axis.Cancer Biol Ther. 2019;20(3):261-271. doi: 10.1080/15384047.2018.1529091. Epub 2018 Nov 27.
• [8] 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.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] Gene expression profiling analysis of bisphenol A-induced perturbation in biological processes in ER-negative HEK293 cells. PLoS One. 2014 Jun 5;9(6):e98635.