Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD5KR2J)

• DOT Name: Tyrosine-protein kinase BAZ1B (BAZ1B)
• Synonyms: EC 2.7.10.2; Bromodomain adjacent to zinc finger domain protein 1B; Williams syndrome transcription factor; Williams-Beuren syndrome chromosomal region 10 protein; Williams-Beuren syndrome chromosomal region 9 protein; hWALp2
• Gene Name: BAZ1B
• Related Disease:
  Hypercalcaemia
  Non-insulin dependent diabetes
  Advanced cancer
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Gout
  Prostate neoplasm
  Stroke
  Type-1/2 diabetes
  Gastric cancer
  Stomach cancer
  Autism spectrum disorder
  Lung cancer
  Lung carcinoma
  Migraine disorder
• UniProt ID: BAZ1B_HUMAN
• PDB ID: 1F62; 5NNF
• EC Number: 2.7.10.2
• Pfam ID: PF00439 ; PF00628 ; PF10537 ; PF15612 ; PF15613
• Sequence:
  MAPLLGRKPFPLVKPLPGEEPLFTIPHTQEAFRTREEYEARLERYSERIWTCKSTGSSQL
  THKEAWEEEQEVAELLKEEFPAWYEKLVLEMVHHNTASLEKLVDTAWLEIMTKYAVGEEC
  DFEVGKEKMLKVKIVKIHPLEKVDEEATEKKSDGACDSPSSDKENSSQIAQDHQKKETVV
  KEDEGRRESINDRARRSPRKLPTSLKKGERKWAPPKFLPHKYDVKLQNEDKIISNVPADS
  LIRTERPPNKEIVRYFIRHNALRAGTGENAPWVVEDELVKKYSLPSKFSDFLLDPYKYMT
  LNPSTKRKNTGSPDRKPSKKSKTDNSSLSSPLNPKLWCHVHLKKSLSGSPLKVKNSKNSK
  SPEEHLEEMMKMMSPNKLHTNFHIPKKGPPAKKPGKHSDKPLKAKGRSKGILNGQKSTGN
  SKSPKKGLKTPKTKMKQMTLLDMAKGTQKMTRAPRNSGGTPRTSSKPHKHLPPAALHLIA
  YYKENKDREDKRSALSCVISKTARLLSSEDRARLPEELRSLVQKRYELLEHKKRWASMSE
  EQRKEYLKKKREELKKKLKEKAKERREKEMLERLEKQKRYEDQELTGKNLPAFRLVDTPE
  GLPNTLFGDVAMVVEFLSCYSGLLLPDAQYPITAVSLMEALSADKGGFLYLNRVLVILLQ
  TLLQDEIAEDYGELGMKLSEIPLTLHSVSELVRLCLRRSDVQEESEGSDTDDNKDSAAFE
  DNEVQDEFLEKLETSEFFELTSEEKLQILTALCHRILMTYSVQDHMETRQQMSAELWKER
  LAVLKEENDKKRAEKQKRKEMEAKNKENGKVENGLGKTDRKKEIVKFEPQVDTEAEDMIS
  AVKSRRLLAIQAKKEREIQEREMKVKLERQAEEERIRKHKAAAEKAFQEGIAKAKLVMRR
  TPIGTDRNHNRYWLFSDEVPGLFIEKGWVHDSIDYRFNHHCKDHTVSGDEDYCPRSKKAN
  LGKNASMNTQHGTATEVAVETTTPKQGQNLWFLCDSQKELDELLNCLHPQGIRESQLKER
  LEKRYQDIIHSIHLARKPNLGLKSCDGNQELLNFLRSDLIEVATRLQKGGLGYVEETSEF
  EARVISLEKLKDFGECVIALQASVIKKFLQGFMAPKQKRRKLQSEDSAKTEEVDEEKKMV
  EEAKVASALEKWKTAIREAQTFSRMHVLLGMLDACIKWDMSAENARCKVCRKKGEDDKLI
  LCDECNKAFHLFCLRPALYEVPDGEWQCPACQPATARRNSRGRNYTEESASEDSEDDESD
  EEEEEEEEEEEEEDYEVAGLRLRPRKTIRGKHSVIPPAARSGRRPGKKPHSTRRSQPKAP
  PVDDAEVDELVLQTKRSSRRQSLELQKCEEILHKIVKYRFSWPFREPVTRDEAEDYYDVI
  THPMDFQTVQNKCSCGSYRSVQEFLTDMKQVFTNAEVYNCRGSHVLSCMVKTEQCLVALL
  HKHLPGHPYVRRKRKKFPDRLAEDEGDSEPEAVGQSRGRRQKK
• Function: Atypical tyrosine-protein kinase that plays a central role in chromatin remodeling and acts as a transcription regulator. Involved in DNA damage response by phosphorylating 'Tyr-142' of histone H2AX (H2AXY142ph). H2AXY142ph plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress. Regulatory subunit of the ATP-dependent WICH-1 and WICH-5 ISWI chromatin remodeling complexes, which form ordered nucleosome arrays on chromatin and facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair. Both complexes regulate the spacing of nucleosomes along the chromatin and have the ability to slide mononucleosomes to the center of a DNA template. The WICH-1 ISWI chromatin remodeling complex has a lower ATP hydrolysis rate than the WICH-5 ISWI chromatin remodeling complex. The WICH-5 ISWI chromatin-remodeling complex regulates the transcription of various genes, has a role in RNA polymerase I transcription. Within the B-WICH complex has a role in RNA polymerase III transcription. Mediates the recruitment of the WICH-5 ISWI chromatin remodeling complex to replication foci during DNA replication.
• Tissue Specificity: Ubiquitously expressed with high levels of expression in heart, brain, placenta, skeletal muscle and ovary.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway:
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  B-WICH complex positively regulates rRNA expression (R-HSA-5250924)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypercalcaemia	DISKQ2K7	Definitive	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cardiac failure	DISDC067	Strong	Genetic Variation	[4]
Gout	DISHC0U7	Strong	Genetic Variation	[5]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[6]
Stroke	DISX6UHX	Strong	Genetic Variation	[4]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[4]
Gastric cancer	DISXGOUK	Disputed	Biomarker	[7]
Stomach cancer	DISKIJSX	Disputed	Biomarker	[7]
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[8]
Lung cancer	DISCM4YA	Limited	Biomarker	[9]
Lung carcinoma	DISTR26C	Limited	Biomarker	[9]
Migraine disorder	DISFCQTG	Limited	Genetic Variation	[10]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Uric acid	DMA1MKT	Investigative	Tyrosine-protein kinase BAZ1B (BAZ1B) affects the abundance of Uric acid.	[5]

5 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 Tyrosine-protein kinase BAZ1B (BAZ1B).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Tyrosine-protein kinase BAZ1B (BAZ1B).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tyrosine-protein kinase BAZ1B (BAZ1B).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Tyrosine-protein kinase BAZ1B (BAZ1B).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Tyrosine-protein kinase BAZ1B (BAZ1B).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tyrosine-protein kinase BAZ1B (BAZ1B).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of Tyrosine-protein kinase BAZ1B (BAZ1B).	[13]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Tyrosine-protein kinase BAZ1B (BAZ1B).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Tyrosine-protein kinase BAZ1B (BAZ1B).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tyrosine-protein kinase BAZ1B (BAZ1B).	[16]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Tyrosine-protein kinase BAZ1B (BAZ1B).	[19]

References

• [1] Importance of dietary calcium and vitamin D in the treatment of hypercalcaemia in Williams-Beuren syndrome.J Pediatr Endocrinol Metab. 2014 Jul;27(7-8):757-61. doi: 10.1515/jpem-2013-0229.
• [2] Replication of recently described type 2 diabetes gene variants in a South Indian population.Metabolism. 2010 Dec;59(12):1760-6. doi: 10.1016/j.metabol.2010.04.024. Epub 2010 Jul 2.
• [3] Williams syndrome transcription factor (WSTF) acts as an activator of estrogen receptor signaling in breast cancer cells and the effect can be abrogated by 1,25-dihydroxyvitamin D(3).J Steroid Biochem Mol Biol. 2018 Mar;177:171-178. doi: 10.1016/j.jsbmb.2017.06.003. Epub 2017 Jun 10.
• [4] Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.Front Genet. 2016 Oct 13;7:179. doi: 10.3389/fgene.2016.00179. eCollection 2016.
• [5] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [6] Subnuclear domain proteins in cancer cells support the functions of RUNX2 in the DNA damage response.J Cell Sci. 2015 Feb 15;128(4):728-40. doi: 10.1242/jcs.160051. Epub 2015 Jan 20.
• [7] K-ras-ERK1/2 down-regulates H2A.X(Y142ph) through WSTF to promote the progress of gastric cancer.BMC Cancer. 2019 May 31;19(1):530. doi: 10.1186/s12885-019-5750-x.
• [8] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [9] WSTF promotes proliferation and invasion of lung cancer cells by inducing EMT via PI3K/Akt and IL-6/STAT3 signaling pathways.Cell Signal. 2016 Nov;28(11):1673-82. doi: 10.1016/j.cellsig.2016.07.008. Epub 2016 Jul 21.
• [10] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [20] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.