Details of Drug Off-Target (DOT)

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

• DOT Name: Transforming acidic coiled-coil-containing protein 3 (TACC3)
• Synonyms: ERIC-1
• Gene Name: TACC3
• UniProt ID: TACC3_HUMAN
• PDB ID: 5LXN; 5LXO; 5ODS; 5ODT
• Pfam ID: PF05010
• Sequence:
  MSLQVLNDKNVSNEKNTENCDFLFSPPEVTGRSSVLRVSQKENVPPKNLAKAMKVTFQTP
  LRDPQTHRILSPSMASKLEAPFTQDDTLGLENSHPVWTQKENQQLIKEVDAKTTHGILQK
  PVEADTDLLGDASPAFGSGSSSESGPGALADLDCSSSSQSPGSSENQMVSPGKVSGSPEQ
  AVEENLSSYSLDRRVTPASETLEDPCRTESQHKAETPHGAEEECKAETPHGAEEECRHGG
  VCAPAAVATSPPGAIPKEACGGAPLQGLPGEALGCPAGVGTPVPADGTQTLTCAHTSAPE
  STAPTNHLVAGRAMTLSPQEEVAAGQMASSSRSGPVKLEFDVSDGATSKRAPPPRRLGER
  SGLKPPLRKAAVRQQKAPQEVEEDDGRSGAGEDPPMPASRGSYHLDWDKMDDPNFIPFGG
  DTKSGCSEAQPPESPETRLGQPAAEQLHAGPATEEPGPCLSQQLHSASAEDTPVVQLAAE
  TPTAESKERALNSASTSLPTSCPGSEPVPTHQQGQPALELKEESFRDPAEVLGTGAEVDY
  LEQFGTSSFKESALRKQSLYLKFDPLLRDSPGRPVPVATETSSMHGANETPSGRPREAKL
  VEFDFLGALDIPVPGPPPGVPAPGGPPLSTGPIVDLLQYSQKDLDAVVKATQEENRELRS
  RCEELHGKNLELGKIMDRFEEVVYQAMEEVQKQKELSKAEIQKVLKEKDQLTTDLNSMEK
  SFSDLFKRFEKQKEVIEGYRKNEESLKKCVEDYLARITQEGQRYQALKAHAEEKLQLANE
  EIAQVRSKAQAEALALQASLRKEQMRIQSLEKTVEQKTKENEELTRICDDLISKMEKI
• Function: Plays a role in the microtubule-dependent coupling of the nucleus and the centrosome. Involved in the processes that regulate centrosome-mediated interkinetic nuclear migration (INM) of neural progenitors. Acts as a component of the TACC3/ch-TOG/clathrin complex proposed to contribute to stabilization of kinetochore fibers of the mitotic spindle by acting as inter-microtubule bridge. The TACC3/ch-TOG/clathrin complex is required for the maintenance of kinetochore fiber tension. May be involved in the control of cell growth and differentiation. May contribute to cancer.
• Reactome Pathway:
  Negative regulation of NOTCH4 signaling (R-HSA-9604323)
  NOTCH3 Activation and Transmission of Signal to the Nucleus (R-HSA-9013507)

Molecular Interaction Atlas (MIA) of This DOT

5 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 Transforming acidic coiled-coil-containing protein 3 (TACC3).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[19]

23 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 Transforming acidic coiled-coil-containing protein 3 (TACC3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[12]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[13]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[15]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[16]
LY2835219	DM93VBZ	Approved	LY2835219 decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[5]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[21]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[23]
AM251	DMTAWHL	Investigative	AM251 decreases the expression of Transforming acidic coiled-coil-containing protein 3 (TACC3).	[24]

References

• [1] 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.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [6] 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.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [13] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [14] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [15] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [16] Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. Oncotarget. 2017 Jul 4;8(27):43678-43691. doi: 10.18632/oncotarget.18435.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [22] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [23] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [24] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.