Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6Q7GR3)

• DOT Name: Centromere protein R (ITGB3BP)
• Synonyms: CENP-R; Beta-3-endonexin; Integrin beta-3-binding protein; Nuclear receptor-interacting factor 3
• Gene Name: ITGB3BP
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Endometriosis
  Neoplasm
• UniProt ID: CENPR_HUMAN
• PDB ID: 7PB8; 7PKN; 7QOO; 7R5S; 7R5V; 7XHN; 7XHO; 7YWX; 7YYH
• Pfam ID: PF06729
• Sequence:
  MPVKRSLKLDGLLEENSFDPSKITRKKSVITYSPTTGTCQMSLFASPTSSEEQKHRNGLS
  NEKRKKLNHPSLTESKESTTKDNDEFMMLLSKVEKLSEEIMEIMQNLSSIQALEGSRELE
  NLIGISCASHFLKREMQKTKELMTKVNKQKLFEKSTGLPHKASRHLDSYEFLKAILN
• Function: Transcription coregulator that can have both coactivator and corepressor functions. Isoform 1, but not other isoforms, is involved in the coactivation of nuclear receptors for retinoid X (RXRs) and thyroid hormone (TRs) in a ligand-dependent fashion. In contrast, it does not coactivate nuclear receptors for retinoic acid, vitamin D, progesterone receptor, nor glucocorticoid. Acts as a coactivator for estrogen receptor alpha. Acts as a transcriptional corepressor via its interaction with the NFKB1 NF-kappa-B subunit, possibly by interfering with the transactivation domain of NFKB1. Induces apoptosis in breast cancer cells, but not in other cancer cells, via a caspase-2 mediated pathway that involves mitochondrial membrane permeabilization but does not require other caspases. May also act as an inhibitor of cyclin A-associated kinase. Also acts a 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.
• Tissue Specificity: Widely expressed. Expressed in spleen, thymus, prostate, ovary, small intestine and white blood cells. Highly expressed in testis and colon. Isoform 4 is expressed in platelets, lymphocytes and granulocytes.
• Reactome Pathway:
  NRIF signals cell death from the nucleus (R-HSA-205043)
  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

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Endometriosis	DISX1AG8	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Centromere protein R (ITGB3BP).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Centromere protein R (ITGB3BP).	[22]

20 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 Centromere protein R (ITGB3BP).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Centromere protein R (ITGB3BP).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Centromere protein R (ITGB3BP).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Centromere protein R (ITGB3BP).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Centromere protein R (ITGB3BP).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Centromere protein R (ITGB3BP).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Centromere protein R (ITGB3BP).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Centromere protein R (ITGB3BP).	[13]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Centromere protein R (ITGB3BP).	[14]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Centromere protein R (ITGB3BP).	[15]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Centromere protein R (ITGB3BP).	[16]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Centromere protein R (ITGB3BP).	[17]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Centromere protein R (ITGB3BP).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Centromere protein R (ITGB3BP).	[19]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Centromere protein R (ITGB3BP).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Centromere protein R (ITGB3BP).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centromere protein R (ITGB3BP).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Centromere protein R (ITGB3BP).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Centromere protein R (ITGB3BP).	[25]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Centromere protein R (ITGB3BP).	[12]

References

• [1] Fas Activated Serine-Threonine Kinase Domains 2 (FASTKD2) mediates apoptosis of breast and prostate cancer cells through its novel FAST2 domain.BMC Cancer. 2014 Nov 20;14:852. doi: 10.1186/1471-2407-14-852.
• [2] The NRIF3 family of transcriptional coregulators induces rapid and profound apoptosis in breast cancer cells.Mol Cell Biol. 2004 May;24(9):3838-48. doi: 10.1128/MCB.24.9.3838-3848.2004.
• [3] Nuclear receptor, coregulator signaling, and chromatin remodeling pathways suggest involvement of the epigenome in the steroid hormone response of endometrium and abnormalities in endometriosis.Reprod Sci. 2012 Feb;19(2):152-62. doi: 10.1177/1933719111415546. Epub 2011 Dec 2.
• [4] CENP-R acts bilaterally as a tumor suppressor and as an oncogene in the two-stage skin carcinogenesis model.Cancer Sci. 2017 Nov;108(11):2142-2148. doi: 10.1111/cas.13348. Epub 2017 Aug 30.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] 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.
• [12] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [15] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [16] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [17] 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.
• [18] Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci. 2007 Jun;98(6):890-9.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [21] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [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] 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.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.