Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT80DZMT)

• DOT Name: Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1)
• Synonyms: hBUB1; EC 2.7.11.1; BUB1A
• Gene Name: BUB1
• Related Disease:
  Mosaic variegated aneuploidy syndrome
  Colorectal cancer
  Microcephaly 30, primary, autosomal recessive
• UniProt ID: BUB1_HUMAN
• PDB ID: 2LAH; 4A1G; 4QPM; 4R8Q; 5DMZ; 6F7B; 7B1F; 7B1H; 7B1J
• EC Number: 2.7.11.1
• Pfam ID: PF08311 ; PF00069
• Sequence:
  MDTPENVLQMLEAHMQSYKGNDPLGEWERYIQWVEENFPENKEYLITLLEHLMKEFLDKK
  KYHNDPRFISYCLKFAEYNSDLHQFFEFLYNHGIGTLSSPLYIAWAGHLEAQGELQHASA
  VLQRGIQNQAEPREFLQQQYRLFQTRLTETHLPAQARTSEPLHNVQVLNQMITSKSNPGN
  NMACISKNQGSELSGVISSACDKESNMERRVITISKSEYSVHSSLASKVDVEQVVMYCKE
  KLIRGESEFSFEELRAQKYNQRRKHEQWVNEDRHYMKRKEANAFEEQLLKQKMDELHKKL
  HQVVETSHEDLPASQERSEVNPARMGPSVGSQQELRAPCLPVTYQQTPVNMEKNPREAPP
  VVPPLANAISAALVSPATSQSIAPPVPLKAQTVTDSMFAVASKDAGCVNKSTHEFKPQSG
  AEIKEGCETHKVANTSSFHTTPNTSLGMVQATPSKVQPSPTVHTKEALGFIMNMFQAPTL
  PDISDDKDEWQSLDQNEDAFEAQFQKNVRSSGAWGVNKIISSLSSAFHVFEDGNKENYGL
  PQPKNKPTGARTFGERSVSRLPSKPKEEVPHAEEFLDDSTVWGIRCNKTLAPSPKSPGDF
  TSAAQLASTPFHKLPVESVHILEDKENVVAKQCTQATLDSCEENMVVPSRDGKFSPIQEK
  SPKQALSSHMYSASLLRLSQPAAGGVLTCEAELGVEACRLTDTDAAIAEDPPDAIAGLQA
  EWMQMSSLGTVDAPNFIVGNPWDDKLIFKLLSGLSKPVSSYPNTFEWQCKLPAIKPKTEF
  QLGSKLVYVHHLLGEGAFAQVYEATQGDLNDAKNKQKFVLKVQKPANPWEFYIGTQLMER
  LKPSMQHMFMKFYSAHLFQNGSVLVGELYSYGTLLNAINLYKNTPEKVMPQGLVISFAMR
  MLYMIEQVHDCEIIHGDIKPDNFILGNGFLEQDDEDDLSAGLALIDLGQSIDMKLFPKGT
  IFTAKCETSGFQCVEMLSNKPWNYQIDYFGVAATVYCMLFGTYMKVKNEGGECKPEGLFR
  RLPHLDMWNEFFHVMLNIPDCHHLPSLDLLRQKLKKVFQQHYTNKIRALRNRLIVLLLEC
  KRSRK
• Function: Serine/threonine-protein kinase that performs 2 crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Has a key role in the assembly of checkpoint proteins at the kinetochore, being required for the subsequent localization of CENPF, BUB1B, CENPE and MAD2L1. Required for the kinetochore localization of PLK1. Required for centromeric enrichment of AUKRB in prometaphase. Plays an important role in defining SGO1 localization and thereby affects sister chromatid cohesion. Promotes the centromeric localization of TOP2A. Acts as a substrate for anaphase-promoting complex or cyclosome (APC/C) in complex with its activator CDH1 (APC/C-Cdh1). Necessary for ensuring proper chromosome segregation and binding to BUB3 is essential for this function. Can regulate chromosome segregation in a kinetochore-independent manner. Can phosphorylate BUB3. The BUB1-BUB3 complex plays a role in the inhibition of APC/C when spindle-assembly checkpoint is activated and inhibits the ubiquitin ligase activity of APC/C by phosphorylating its activator CDC20. This complex can also phosphorylate MAD1L1. Kinase activity is essential for inhibition of APC/CCDC20 and for chromosome alignment but does not play a major role in the spindle-assembly checkpoint activity. Mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis.
• Tissue Specificity: High expression in testis and thymus, less in colon, spleen, lung and small intestine. Expressed in fetal thymus, bone marrow, heart, liver, spleen and thymus. Expression is associated with cells/tissues with a high mitotic index.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  Progesterone-mediated oocyte maturation (hsa04914)
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mosaic variegated aneuploidy syndrome	DIS5QTMU	Supportive	Autosomal dominant	[1]
Colorectal cancer	DISNH7P9	Limited	Autosomal dominant	[2]
Microcephaly 30, primary, autosomal recessive	DISWI9ES	Limited	Unknown	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1) affects the response to substance of Vinblastine.	[45]

44 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 Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[19]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[20]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[21]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[22]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[23]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[24]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[25]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[26]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[27]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[28]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[29]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[30]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[31]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[32]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[36]
Eugenol	DM7US1H	Patented	Eugenol decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[39]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[40]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[41]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[42]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[43]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[44]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[35]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1).	[37]

References

• [1] Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer. Gastroenterology. 2013 Sep;145(3):544-7. doi: 10.1053/j.gastro.2013.06.001. Epub 2013 Jun 5.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation. Sci Adv. 2022 Jan 21;8(3):eabk0114. doi: 10.1126/sciadv.abk0114. Epub 2022 Jan 19.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples. Data Brief. 2016 Mar 26;7:1052-1057. doi: 10.1016/j.dib.2016.03.069. eCollection 2016 Jun.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] 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.
• [13] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] 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.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [18] 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.
• [19] 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.
• [20] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [21] mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer cells at the cell proliferation and gene-expression levels. Cancer Sci. 2008 Oct;99(10):1992-2003. doi: 10.1111/j.1349-7006.2008.00955.x.
• [22] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [23] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [24] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [25] Responses of genes involved in cell cycle control to diverse DNA damaging chemicals in human lung adenocarcinoma A549 cells. Cancer Cell Int. 2005 Aug 24;5:28. doi: 10.1186/1475-2867-5-28.
• [26] 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.
• [27] 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.
• [28] Differential gene expression in normal human mammary epithelial cells treated with malathion monitored by DNA microarrays. Environ Health Perspect. 2005 Aug;113(8):1046-51.
• [29] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [30] 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.
• [31] Resveratrol-induced gene expression profiles in human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):596-604. doi: 10.1158/1055-9965.EPI-04-0398.
• [32] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [33] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [34] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [35] 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.
• [36] 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.
• [37] 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.
• [38] 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.
• [39] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [40] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [41] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [42] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [43] Genome-wide impact of androgen receptor trapped clone-27 loss on androgen-regulated transcription in prostate cancer cells. Cancer Res. 2009 Apr 1;69(7):3140-7. doi: 10.1158/0008-5472.CAN-08-3738. Epub 2009 Mar 24.
• [44] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [45] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.