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

DOT Name Lysine-specific demethylase 6B (KDM6B)
Synonyms EC 1.14.11.68; JmjC domain-containing protein 3; Jumonji domain-containing protein 3; Lysine demethylase 6B; -trimethyl-L-lysine(27) demethylase 6B
Gene Name KDM6B
Related Disease
Syndromic intellectual disability ( )
Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities ( )
UniProt ID
KDM6B_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
2XUE; 2XXZ; 4ASK; 5FP3; 5OY3; 6F6D
EC Number
1.14.11.68
Pfam ID
PF02373 ; PF21322 ; PF21326
Sequence
MHRAVDPPGARAAREAFALGGLSCAGAWSSCPPHPPPRSAWLPGGRCSASIGQPPLPAPL
PPSHGSSSGHPSKPYYAPGAPTPRPLHGKLESLHGCVQALLREPAQPGLWEQLGQLYESE
HDSEEATRCYHSALRYGGSFAELGPRIGRLQQAQLWNFHTGSCQHRAKVLPPLEQVWNLL
HLEHKRNYGAKRGGPPVKRAAEPPVVQPVPPAALSGPSGEEGLSPGGKRRRGCNSEQTGL
PPGLPLPPPPLPPPPPPPPPPPPPLPGLATSPPFQLTKPGLWSTLHGDAWGPERKGSAPP
ERQEQRHSLPHPYPYPAPAYTAHPPGHRLVPAAPPGPGPRPPGAESHGCLPATRPPGSDL
RESRVQRSRMDSSVSPAATTACVPYAPSRPPGLPGTTTSSSSSSSSNTGLRGVEPNPGIP
GADHYQTPALEVSHHGRLGPSAHSSRKPFLGAPAATPHLSLPPGPSSPPPPPCPRLLRPP
PPPAWLKGPACRAAREDGEILEELFFGTEGPPRPAPPPLPHREGFLGPPASRFSVGTQDS
HTPPTPPTPTTSSSNSNSGSHSSSPAGPVSFPPPPYLARSIDPLPRPPSPAQNPQDPPLV
PLTLALPPAPPSSCHQNTSGSFRRPESPRPRVSFPKTPEVGPGPPPGPLSKAPQPVPPGV
GELPARGPRLFDFPPTPLEDQFEEPAEFKILPDGLANIMKMLDESIRKEEEQQQHEAGVA
PQPPLKEPFASLQSPFPTDTAPTTTAPAVAVTTTTTTTTTTTATQEEEKKPPPALPPPPP
LAKFPPPSQPQPPPPPPPSPASLLKSLASVLEGQKYCYRGTGAAVSTRPGPLPTTQYSPG
PPSGATALPPTSAAPSAQGSPQPSASSSSQFSTSGGPWARERRAGEEPVPGPMTPTQPPP
PLSLPPARSESEVLEEISRACETLVERVGRSATDPADPVDTAEPADSGTERLLPPAQAKE
EAGGVAAVSGSCKRRQKEHQKEHRRHRRACKDSVGRRPREGRAKAKAKVPKEKSRRVLGN
LDLQSEEIQGREKSRPDLGGASKAKPPTAPAPPSAPAPSAQPTPPSASVPGKKAREEAPG
PPGVSRADMLKLRSLSEGPPKELKIRLIKVESGDKETFIASEVEERRLRMADLTISHCAA
DVVRASRNAKVKGKFRESYLSPAQSVKPKINTEEKLPREKLNPPTPSIYLESKRDAFSPV
LLQFCTDPRNPITVIRGLAGSLRLNLGLFSTKTLVEASGEHTVEVRTQVQQPSDENWDLT
GTRQIWPCESSRSHTTIAKYAQYQASSFQESLQEEKESEDEESEEPDSTTGTPPSSAPDP
KNHHIIKFGTNIDLSDAKRWKPQLQELLKLPAFMRVTSTGNMLSHVGHTILGMNTVQLYM
KVPGSRTPGHQENNNFCSVNINIGPGDCEWFAVHEHYWETISAFCDRHGVDYLTGSWWPI
LDDLYASNIPVYRFVQRPGDLVWINAGTVHWVQATGWCNNIAWNVGPLTAYQYQLALERY
EWNEVKNVKSIVPMIHVSWNVARTVKISDPDLFKMIKFCLLQSMKHCQVQRESLVRAGKK
IAYQGRVKDEPAYYCNECDVEVFNILFVTSENGSRNTYLVHCEGCARRRSAGLQGVVVLE
QYRTEELAQAYDAFTLAPASTSR
Function
Histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code. Demethylates trimethylated and dimethylated H3 'Lys-27'. Plays a central role in regulation of posterior development, by regulating HOX gene expression. Involved in inflammatory response by participating in macrophage differentiation in case of inflammation by regulating gene expression and macrophage differentiation. Plays a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression by acting as a link between T-box factors and the SMARCA4-containing SWI/SNF remodeling complex.
Reactome Pathway
HDMs demethylate histones (R-HSA-3214842 )
Chromatin modifications during the maternal to zygotic transition (MZT) (R-HSA-9821002 )
Oxidative Stress Induced Senescence (R-HSA-2559580 )
BioCyc Pathway
MetaCyc:ENSG00000132510-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Syndromic intellectual disability DISH7SDF Definitive Autosomal dominant [1]
Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities DIS094OL Strong Autosomal dominant [2]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the methylation of Lysine-specific demethylase 6B (KDM6B). [3]
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16 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Lysine-specific demethylase 6B (KDM6B). [4]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Lysine-specific demethylase 6B (KDM6B). [5]
Doxorubicin DMVP5YE Approved Doxorubicin increases the expression of Lysine-specific demethylase 6B (KDM6B). [6]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Lysine-specific demethylase 6B (KDM6B). [7]
Vorinostat DMWMPD4 Approved Vorinostat decreases the expression of Lysine-specific demethylase 6B (KDM6B). [8]
Selenium DM25CGV Approved Selenium increases the expression of Lysine-specific demethylase 6B (KDM6B). [9]
Niclosamide DMJAGXQ Approved Niclosamide increases the expression of Lysine-specific demethylase 6B (KDM6B). [10]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Lysine-specific demethylase 6B (KDM6B). [11]
Berberine DMC5Q8X Phase 4 Berberine increases the expression of Lysine-specific demethylase 6B (KDM6B). [12]
SNDX-275 DMH7W9X Phase 3 SNDX-275 decreases the expression of Lysine-specific demethylase 6B (KDM6B). [13]
Tocopherol DMBIJZ6 Phase 2 Tocopherol increases the expression of Lysine-specific demethylase 6B (KDM6B). [9]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of Lysine-specific demethylase 6B (KDM6B). [14]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Lysine-specific demethylase 6B (KDM6B). [15]
UNC0379 DMD1E4J Preclinical UNC0379 decreases the expression of Lysine-specific demethylase 6B (KDM6B). [16]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Lysine-specific demethylase 6B (KDM6B). [8]
Nickel chloride DMI12Y8 Investigative Nickel chloride increases the expression of Lysine-specific demethylase 6B (KDM6B). [17]
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⏷ Show the Full List of 16 Drug(s)

References

1 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.
2 Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features. Am J Med Genet A. 2019 Jul;179(7):1276-1286. doi: 10.1002/ajmg.a.61173. Epub 2019 May 23.
3 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.
4 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.
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 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.
7 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
8 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.
9 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.
10 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.
11 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
12 Berberine acts as a putative epigenetic modulator by affecting the histone code. Toxicol In Vitro. 2016 Oct;36:10-17. doi: 10.1016/j.tiv.2016.06.004. Epub 2016 Jun 13.
13 A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
14 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
15 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.
16 Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
17 The regulatory role of nickel on H3K27 demethylase JMJD3 in kidney cancer cells. Toxicol Ind Health. 2016 Jul;32(7):1286-92. doi: 10.1177/0748233714552687. Epub 2014 Nov 26.