Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUI8QK3)

• DOT Name: Cell division cycle-associated protein 3 (CDCA3)
• Synonyms: Gene-rich cluster protein C8; Trigger of mitotic entry protein 1; TOME-1
• Gene Name: CDCA3
• Related Disease:
  Acute myelogenous leukaemia
  Hepatocellular carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Oral cancer
  Advanced cancer
  Colorectal carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Gastric cancer
  Liver cancer
  Myopia
  Stomach cancer
• UniProt ID: CDCA3_HUMAN
• Sequence:
  MGSAKSVPVTPARPPPHNKHLARVADPRSPSAGILRTPIQVESSPQPGLPAGEQLEGLKH
  AQDSDPRSPTLGIARTPMKTSSGDPPSPLVKQLSEVFETEDSKSNLPPEPVLPPEAPLSS
  ELDLPLGTQLSVEEQMPPWNQTEFPSKQVFSKEEARQPTETPVASQSSDKPSRDPETPRS
  SGSMRNRWKPNSSKVLGRSPLTILQDDNSPGTLTLRQGKRPSPLSENVSELKEGAILGTG
  RLLKTGGRAWEQGQDHDKENQHFPLVES
• Function: F-box-like protein which is required for entry into mitosis. Acts by participating in E3 ligase complexes that mediate the ubiquitination and degradation of WEE1 kinase at G2/M phase.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[4]
Oral cancer	DISLD42D	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[8]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[9]
Liver cancer	DISDE4BI	Limited	Biomarker	[8]
Myopia	DISK5S60	Limited	Genetic Variation	[10]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[9]

32 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 Cell division cycle-associated protein 3 (CDCA3).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Cell division cycle-associated protein 3 (CDCA3).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cell division cycle-associated protein 3 (CDCA3).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[18]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[21]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[22]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[22]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Cell division cycle-associated protein 3 (CDCA3).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cell division cycle-associated protein 3 (CDCA3).	[24]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Cell division cycle-associated protein 3 (CDCA3).	[16]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[25]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[26]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[27]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[28]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[29]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[30]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[31]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[32]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[34]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[35]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[36]
TAK-114	DMTXE19	Phase 1	TAK-114 decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[38]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cell division cycle-associated protein 3 (CDCA3).	[39]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cell division cycle-associated protein 3 (CDCA3).	[17]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the expression of Cell division cycle-associated protein 3 (CDCA3).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cell division cycle-associated protein 3 (CDCA3).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Cell division cycle-associated protein 3 (CDCA3).	[40]

References

• [1] A novel miR-375-HOXB3-CDCA3/DNMT3B regulatory circuitry contributes to leukemogenesis in acute myeloid leukemia.BMC Cancer. 2018 Feb 13;18(1):182. doi: 10.1186/s12885-018-4097-z.
• [2] Silymarin-mediated regulation of the cell cycle and DNA damage response exerts antitumor activity in human hepatocellular carcinoma.Oncol Lett. 2018 Jan;15(1):885-892. doi: 10.3892/ol.2017.7425. Epub 2017 Nov 15.
• [3] CDCA3 is a potential prognostic marker that promotes cell proliferation in gastric cancer.Oncol Rep. 2019 Apr;41(4):2471-2481. doi: 10.3892/or.2019.7008. Epub 2019 Feb 12.
• [4] Expression of CDCA3 Is a Prognostic Biomarker andPotential Therapeutic Target in Non-Small CellLungCancer.J Thorac Oncol. 2017 Jul;12(7):1071-1084. doi: 10.1016/j.jtho.2017.04.018. Epub 2017 May 6.
• [5] Overexpression of cell cycle regulator CDCA3 promotes oral cancer progression by enhancing cell proliferation with prevention of G1 phase arrest.BMC Cancer. 2012 Jul 28;12:321. doi: 10.1186/1471-2407-12-321.
• [6] CDCA3 mediates p21-dependent proliferation by regulating E2F1 expression in colorectal cancer.Int J Oncol. 2018 Nov;53(5):2021-2033. doi: 10.3892/ijo.2018.4538. Epub 2018 Aug 23.
• [7] CDCA3 promotes cell proliferation by activating the NF-B/cyclin D1 signaling pathway in colorectal cancer.Biochem Biophys Res Commun. 2018 Jun 2;500(2):196-203. doi: 10.1016/j.bbrc.2018.04.034. Epub 2018 Apr 14.
• [8] OY-TES-1 may regulate the malignant behavior of liver cancer via NANOG, CD9, CCND2 and CDCA3: a bioinformatic analysis combine with RNAi and oligonucleotide microarray.Oncol Rep. 2015 Apr;33(4):1965-75. doi: 10.3892/or.2015.3792. Epub 2015 Feb 10.
• [9] DNA hypomethylation promotes invasion and metastasis of gastric cancer cells by regulating the binding of SP1 to the CDCA3 promoter.J Cell Biochem. 2020 Jan;121(1):142-151. doi: 10.1002/jcb.28993. Epub 2019 Jun 18.
• [10] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [11] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [12] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [13] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] 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.
• [16] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] 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.
• [19] 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.
• [20] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [21] 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.
• [22] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [23] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [24] 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.
• [25] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [28] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [29] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [30] 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.
• [31] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [32] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [33] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [34] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [35] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [36] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [37] In silico, in vitro and in vivo studies: Dibutyl phthalate promotes prostate cancer cell proliferation by activating Forkhead Box M1 and remission after Natura- pretreatment. Toxicology. 2023 Apr;488:153465. doi: 10.1016/j.tox.2023.153465. Epub 2023 Feb 23.
• [38] 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.
• [39] 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.
• [40] 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.