Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXAH83Y)

• DOT Name: Centromere protein O (CENPO)
• Synonyms: CENP-O; Interphase centromere complex protein 36
• Gene Name: CENPO
• Related Disease:
  Advanced cancer
  Gastric cancer
  Multiple sclerosis
  Stomach cancer
  Coronary heart disease
  Bladder cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: CENPO_HUMAN
• PDB ID: 7PB8; 7PKN; 7QOO; 7R5S; 7R5V; 7XHN; 7XHO; 7YWX; 7YYH
• Pfam ID: PF09496
• Sequence:
  MEQANPLRPDGESKGGVLAHLERLETQVSRSRKQSEELQSVQAQEGALGTKIHKLRRLRD
  ELRAVVRHRRASVKACIANVEPNQTVEINEQEALEEKLENVKAILQAYHFTGLSGKLTSR
  GVCVCISTAFEGNLLDSYFVDLVIQKPLRIHHHSVPVFIPLEEIAAKYLQTNIQHFLFSL
  CEYLNAYSGRKYQADRLQSDFAALLTGPLQRNPLCNLLSFTYKLDPGGQSFPFCARLLYK
  DLTATLPTDVTVTCQGVEVLSTSWEEQRASHETLFCTKPLHQVFASFTRKGEKLDMSLVS
• Function: Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex. Modulates the kinetochore-bound levels of NDC80 complex.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  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

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[2]
Stomach cancer	DISKIJSX	Strong	Biomarker	[1]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[3]
Bladder cancer	DISUHNM0	Limited	Altered Expression	[4]
Urinary bladder cancer	DISDV4T7	Limited	Altered Expression	[4]
Urinary bladder neoplasm	DIS7HACE	Limited	Altered Expression	[4]

13 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 Centromere protein O (CENPO).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Centromere protein O (CENPO).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Centromere protein O (CENPO).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Centromere protein O (CENPO).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Centromere protein O (CENPO).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Centromere protein O (CENPO).	[9]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Centromere protein O (CENPO).	[10]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Centromere protein O (CENPO).	[11]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Centromere protein O (CENPO).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Centromere protein O (CENPO).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centromere protein O (CENPO).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Centromere protein O (CENPO).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Centromere protein O (CENPO).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Centromere protein O (CENPO).	[15]

References

• [1] CENPO expression regulates gastric cancer cell proliferation and is associated with poor patient prognosis.Mol Med Rep. 2019 Oct;20(4):3661-3670. doi: 10.3892/mmr.2019.10624. Epub 2019 Aug 29.
• [2] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [3] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [4] Analysis of Gene Expression in Bladder Cancer: Possible Involvement of Mitosis and Complement and Coagulation Cascades Signaling Pathway.J Comput Biol. 2020 Jun;27(6):987-998. doi: 10.1089/cmb.2019.0237. Epub 2019 Sep 23.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] 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.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] 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.
• [11] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [12] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [13] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.