Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9HFRYK)

• DOT Name: Inner centromere protein (INCENP)
• Gene Name: INCENP
• Related Disease:
  Advanced cancer
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Epithelial ovarian cancer
  Familial prostate carcinoma
  Gastric cancer
  Nephronophthisis
  Neuroblastoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate cancer, hereditary, 1
  Prostate carcinoma
  Stomach cancer
  Colorectal carcinoma
  Melanoma
• UniProt ID: INCE_HUMAN
• PDB ID: 2QFA; 4AF3; 5IEH; 5IEK; 6GR8; 6GR9; 6YIE; 6YIF; 6YIH
• Pfam ID: PF03941 ; PF12178
• Sequence:
  MGTTAPGPIHLLELCDQKLMEFLCNMDNKDLVWLEEIQEEAERMFTREFSKEPELMPKTP
  SQKNRRKKRRISYVQDENRDPIRRRLSRRKSRSSQLSSRRLRSKDSVEKLATVVGENGSV
  LRRVTRAAAAAAAATMALAAPSSPTPESPTMLTKKPEDNHTQCQLVPVVEIGISERQNAE
  QHVTQLMSTEPLPRTLSPTPASATAPTSQGIPTSDEESTPKKSKARILESITVSSLMATP
  QDPKGQGVGTGRSASKLRIAQVSPGPRDSPAFPDSPWRERVLAPILPDNFSTPTGSRTDS
  QSVRHSPIAPSSPSPQVLAQKYSLVAKQESVVRRASRRLAKKTAEEPAASGRIICHSYLE
  RLLNVEVPQKVGSEQKEPPEEAEPVAAAEPEVPENNGNNSWPHNDTEIANSTPNPKPAAS
  SPETPSAGQQEAKTDQADGPREPPQSARRKRSYKQAVSELDEEQHLEDEELQPPRSKTPS
  SPCPASKVVRPLRTFLHTVQRNQMLMTPTSAPRSVMKSFIKRNTPLRMDPKCSFVEKERQ
  RLENLRRKEEAEQLRRQKVEEDKRRRLEEVKLKREERLRKVLQARERVEQMKEEKKKQIE
  QKFAQIDEKTEKAKEERLAEEKAKKKAAAKKMEEVEARRKQEEEARRLRWLQQEEEERRH
  QELLQKKKEEEQERLRKAAEAKRLAEQREQERREQERREQERREQERREQERREQERQLA
  EQERRREQERLQAERELQEREKALRLQKEQLQRELEEKKKKEEQQRLAERQLQEEQEKKA
  KEAAGASKALNVTVDVQSPACTSYQMTPQGHRAPPKINPDNYGMDLNSDDSTDDEAHPRK
  PIPTWARGTPLSQAIIHQYYHPPNLLELFGTILPLDLEDIFKKSKPRYHKRTSSAVWNSP
  PLQGARVPSSLAYSLKKH
• Function: Component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Acts as a scaffold regulating CPC localization and activity. The C-terminus associates with AURKB or AURKC, the N-terminus associated with BIRC5/survivin and CDCA8/borealin tethers the CPC to the inner centromere, and the microtubule binding activity within the central SAH domain directs AURKB/C toward substrates near microtubules. The flexibility of the SAH domain is proposed to allow AURKB/C to follow substrates on dynamic microtubules while ensuring CPC docking to static chromatin. Activates AURKB and AURKC. Required for localization of CBX5 to mitotic centromeres. Controls the kinetochore localization of BUB1.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  SUMOylation of DNA replication proteins (R-HSA-4615885)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[1]
Familial prostate carcinoma	DISL9KNO	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Nephronophthisis	DISXU4HY	Strong	Genetic Variation	[7]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[8]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[1]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[1]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[1]
Prostate cancer, hereditary, 1	DISE2P4L	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[5]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[6]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[9]
Melanoma	DIS1RRCY	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Inner centromere protein (INCENP).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inner centromere protein (INCENP).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Inner centromere protein (INCENP).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Inner centromere protein (INCENP).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Inner centromere protein (INCENP).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Inner centromere protein (INCENP).	[17]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Inner centromere protein (INCENP).	[17]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Inner centromere protein (INCENP).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Inner centromere protein (INCENP).	[19]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Inner centromere protein (INCENP).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Inner centromere protein (INCENP).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Inner centromere protein (INCENP).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Inner centromere protein (INCENP).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Inner centromere protein (INCENP).	[26]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Inner centromere protein (INCENP).	[27]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Inner centromere protein (INCENP).	[28]

5 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 Inner centromere protein (INCENP).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Inner centromere protein (INCENP).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Inner centromere protein (INCENP).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Inner centromere protein (INCENP).	[25]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Inner centromere protein (INCENP).	[24]

References

• [1] Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.Cancer Discov. 2016 Sep;6(9):1052-67. doi: 10.1158/2159-8290.CD-15-1227. Epub 2016 Jul 17.
• [2] Integrative analysis of transcriptome-wide association study data and mRNA expression profiles identified candidate genes and pathways associated with atrial fibrillation.Heart Vessels. 2019 Nov;34(11):1882-1888. doi: 10.1007/s00380-019-01418-w. Epub 2019 May 7.
• [3] Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.Carcinogenesis. 2015 Feb;36(2):256-71. doi: 10.1093/carcin/bgu326. Epub 2015 Jan 13.
• [4] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [5] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [6] Borealin/Dasra B is a cell cycle-regulated chromosomal passenger protein and its nuclear accumulation is linked to poor prognosis for human gastric cancer.Exp Cell Res. 2006 Apr 15;312(7):962-73. doi: 10.1016/j.yexcr.2005.12.015. Epub 2006 Jan 19.
• [7] Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity.Kidney Int. 2016 Feb;89(2):468-475. doi: 10.1038/ki.2015.317.
• [8] Functional high-throughput screening reveals miR-323a-5p and miR-342-5p as new tumor-suppressive microRNA for neuroblastoma.Cell Mol Life Sci. 2019 Jun;76(11):2231-2243. doi: 10.1007/s00018-019-03041-4. Epub 2019 Feb 15.
• [9] Human INCENP colocalizes with the Aurora-B/AIRK2 kinase on chromosomes and is overexpressed in tumour cells.Chromosoma. 2001 May;110(2):65-74. doi: 10.1007/s004120100130.
• [10] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] 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.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Gene expression-signature of belinostat in cell lines is specific for histone deacetylase inhibitor treatment, with a corresponding signature in xenografts. Anticancer Drugs. 2009 Sep;20(8):682-92.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [27] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.
• [28] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.