Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKPUF8K)

• DOT Name: Centromere protein K (CENPK)
• Synonyms: CENP-K; Interphase centromere complex protein 37; Protein AF-5alpha; p33
• Gene Name: CENPK
• Related Disease:
  Alzheimer disease
  Amyloidosis
  Breast cancer
  Breast carcinoma
  Carcinoma
  Neoplasm
  Retinitis pigmentosa
  Triple negative breast cancer
  Retinopathy
  Hepatocellular carcinoma
• UniProt ID: CENPK_HUMAN
• PDB ID: 7PB4; 7PKN; 7QOO; 7R5S; 7R5V; 7XHN; 7XHO; 7YWX; 7YYH
• Pfam ID: PF11802
• Sequence:
  MNQEDLDPDSTTDVGDVTNTEEELIRECEEMWKDMEECQNKLSLIGTETLTDSNAQLSLL
  IMQVKCLTAELSQWQKKTPETIPLTEDVLITLGKEEFQKLRQDLEMVLSTKESKNEKLKE
  DLEREQRWLDEQQQIMESLNVLHSELKNKVETFSESRIFNELKTKMLNIKEYKEKLLSTL
  GEFLEDHFPLPDRSVKKKKKNIQESSVNLITLHEMLEILINRLFDVPHDPYVKISDSFWP
  PYVELLLRNGIALRHPEDPTRIRLEAFHQ
• 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. Acts in coordination with KNL1 to recruit the NDC80 complex to the outer kinetochore.
• Tissue Specificity: Detected in several fetal organs with highest levels in fetal liver. In adults, it is weakly expressed in lung and placenta.
• 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

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Amyloidosis	DISHTAI2	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Carcinoma	DISH9F1N	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[4]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[5]
Retinopathy	DISB4B0F	moderate	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Centromere protein K (CENPK).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Centromere protein K (CENPK).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Centromere protein K (CENPK).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Centromere protein K (CENPK).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Centromere protein K (CENPK).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Centromere protein K (CENPK).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Centromere protein K (CENPK).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Centromere protein K (CENPK).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Centromere protein K (CENPK).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Centromere protein K (CENPK).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Centromere protein K (CENPK).	[17]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Centromere protein K (CENPK).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Centromere protein K (CENPK).	[18]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Centromere protein K (CENPK).	[19]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Centromere protein K (CENPK).	[20]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Centromere protein K (CENPK).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Centromere protein K (CENPK).	[22]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Centromere protein K (CENPK).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Centromere protein K (CENPK).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Centromere protein K (CENPK).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centromere protein K (CENPK).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Centromere protein K (CENPK).	[27]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Centromere protein K (CENPK).	[28]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Centromere protein K (CENPK).	[15]

References

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• [3] Downregulation of CENPK suppresses hepatocellular carcinoma malignant progression through regulating YAP1.Onco Targets Ther. 2019 Jan 29;12:869-882. doi: 10.2147/OTT.S190061. eCollection 2019.
• [4] (Z)-7,4'-Dimethoxy-6-hydroxy-aurone-4-O--glucopyranoside mitigates retinal degeneration in Rd10 mouse model through inhibiting oxidative stress and inflammatory responses.Cutan Ocul Toxicol. 2020 Mar;39(1):36-42. doi: 10.1080/15569527.2019.1685535. Epub 2019 Nov 6.
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• [11] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Global gene expression profiles induced by phytoestrogens in human breast cancer cells. Endocr Relat Cancer. 2008 Mar;15(1):161-73.
• [15] 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.
• [16] 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.
• [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] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [19] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [20] 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.
• [21] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] 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.
• [24] Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands. Toxicol Lett. 2011 Oct 10;206(2):178-88.
• [25] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [26] 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.
• [27] 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.
• [28] 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.