Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZU5J5S)

• DOT Name: Lysine-specific demethylase 3B (KDM3B)
• Synonyms: EC 1.14.11.65; JmjC domain-containing histone demethylation protein 2B; Jumonji domain-containing protein 1B; Nuclear protein 5qNCA; -dimethyl-L-lysine(9) demethylase 3B
• Gene Name: KDM3B
• Related Disease:
  leukaemia
  Leukemia
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Atrichia with papular lesions
  Childhood acute lymphoblastic leukemia
  Colorectal carcinoma
  Diets-Jongmans syndrome
  Haematological malignancy
  Hepatocellular carcinoma
  Myeloid leukaemia
  Neoplasm
  Promyelocytic leukaemia
  Schizophrenia
  Anxiety disorder
  Intellectual disability
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Castration-resistant prostate carcinoma
  Prostate carcinoma
• UniProt ID: KDM3B_HUMAN
• PDB ID: 4C8D ; 5R7X ; 5RAA ; 5RAB ; 5RAC ; 5RAD ; 5RAE ; 5RAF ; 5RAG ; 5RAH ; 5RAI ; 5RAJ ; 5RAK ; 5RAL ; 5RAM ; 5RAN ; 5RAO ; 5RAP ; 5RAQ ; 5RAR ; 5RAS ; 5RAU ; 5RAV ; 5RAW ; 5RAX ; 5RAY ; 5RAZ ; 5RB0 ; 5RB1 ; 5RB2 ; 5RB3 ; 5RB4 ; 5RB5 ; 5RB6 ; 5RB7 ; 6RBJ
• EC Number: 1.14.11.65
• Pfam ID: PF02373
• Sequence:
  MADAAASPVGKRLLLLFADTAASASASAPAAAAASGDPGPALRTRAWRAGTVRAMSGAVP
  QDLAIFVEFDGCNWKQHSWVKVHAEEVIVLLLEGSLVWAPREDPVLLQGIRVSIAQWPAL
  TFTPLVDKLGLGSVVPVEYLLDRELRFLSDANGLHLFQMGTDSQNQILLEHAALRETVNA
  LISDQKLQEIFSRGPYSVQGHRVKIYQPEGEEGWLYGVVSHQDSITRLMEVSVTESGEIK
  SVDPRLIHVMLMDNSAPQSEGGTLKAVKSSKGKKKRESIEGKDGRRRKSASDSGCDPASK
  KLKGDRGEVDSNGSDGGEASRGPWKGGNASGEPGLDQRAKQPPSTFVPQINRNIRFATYT
  KENGRTLVVQDEPVGGDTPASFTPYSTATGQTPLAPEVGGAENKEAGKTLEQVGQGIVAS
  AAVVTTASSTPNTVRISDTGLAAGTVPEKQKGSRSQASGENSRNSILASSGFGAPLPSSS
  QPLTFGSGRSQSNGVLATENKPLGFSFGCSSAQEAQKDTDLSKNLFFQCMSQTLPTSNYF
  TTVSESLADDSSSRDSFKQSLESLSSGLCKGRSVLGTDTKPGSKAGSSVDRKVPAESMPT
  LTPAFPRSLLNARTPENHENLFLQPPKLSREEPSNPFLAFVEKVEHSPFSSFASQASGSS
  SSATTVTSKVAPSWPESHSSADSASLAKKKPLFITTDSSKLVSGVLGSALTSGGPSLSAM
  GNGRSSSPTSSLTQPIEMPTLSSSPTEERPTVGPGQQDNPLLKTFSNVFGRHSGGFLSSP
  ADFSQENKAPFEAVKRFSLDERSLACRQDSDSSTNSDLSDLSDSEEQLQAKTGLKGIPEH
  LMGKLGPNGERSAELLLGKSKGKQAPKGRPRTAPLKVGQSVLKDVSKVKKLKQSGEPFLQ
  DGSCINVAPHLHKCRECRLERYRKFKEQEQDDSTVACRFFHFRRLIFTRKGVLRVEGFLS
  PQQSDPDAMNLWIPSSSLAEGIDLETSKYILANVGDQFCQLVMSEKEAMMMVEPHQKVAW
  KRAVRGVREMCDVCETTLFNIHWVCRKCGFGVCLDCYRLRKSRPRSETEEMGDEEVFSWL
  KCAKGQSHEPENLMPTQIIPGTALYNIGDMVHAARGKWGIKANCPCISRQNKSVLRPAVT
  NGMSQLPSINPSASSGNETTFSGGGGPAPVTTPEPDHVPKADSTDIRSEEPLKTDSSASN
  SNSELKAIRPPCPDTAPPSSALHWLADLATQKAKEETKEAGSLRSVLNKESHSPFGLDSF
  NSTAKVSPLTPKLFNSLLLGPTASNNKTEGSSLRDLLHSGPGKLPQTPLDTGIPFPPVFS
  TSSAGVKSKASLPNFLDHIIASVVENKKTSDASKRACNLTDTQKEVKEMVMGLNVLDPHT
  SHSWLCDGRLLCLHDPSNKNNWKIFRECWKQGQPVLVSGVHKKLKSELWKPEAFSQEFGD
  QDVDLVNCRNCAIISDVKVRDFWDGFEIICKRLRSEDGQPMVLKLKDWPPGEDFRDMMPT
  RFEDLMENLPLPEYTKRDGRLNLASRLPSYFVRPDLGPKMYNAYGLITAEDRRVGTTNLH
  LDVSDAVNVMVYVGIPIGEGAHDEEVLKTIDEGDADEVTKQRIHDGKEKPGALWHIYAAK
  DAEKIRELLRKVGEEQGQENPPDHDPIHDQSWYLDQTLRKRLYEEYGVQGWAIVQFLGDA
  VFIPAGAPHQVHNLYSCIKVAEDFVSPEHVKHCFRLTQEFRHLSNTHTNHEDKLQVKNII
  YHAVKDAVGTLKAHESKLARS
• Function: Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Demethylation of Lys residue generates formaldehyde and succinate. May have tumor suppressor activity.
• Tissue Specificity: Ubiquitous. Highly expressed in placenta, skeletal muscle, kidney, heart and liver.
• KEGG Pathway: Thermogenesis (hsa04714)
• Reactome Pathway: HDMs demethylate histones (R-HSA-3214842)
• BioCyc Pathway: MetaCyc:ENSG00000120733-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
leukaemia	DISS7D1V	Definitive	Biomarker	[1]
Leukemia	DISNAKFL	Definitive	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Atrichia with papular lesions	DIS80CUB	Strong	Biomarker	[3]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Diets-Jongmans syndrome	DIS91YOK	Strong	Autosomal dominant	[5]
Haematological malignancy	DISCDP7W	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[8]
Anxiety disorder	DISBI2BT	moderate	Biomarker	[9]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[5]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[10]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[11]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[11]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Limited	Genetic Variation	[13]

4 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 Lysine-specific demethylase 3B (KDM3B).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Lysine-specific demethylase 3B (KDM3B).	[20]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Lysine-specific demethylase 3B (KDM3B).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Lysine-specific demethylase 3B (KDM3B).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lysine-specific demethylase 3B (KDM3B).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysine-specific demethylase 3B (KDM3B).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lysine-specific demethylase 3B (KDM3B).	[17]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Lysine-specific demethylase 3B (KDM3B).	[18]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide increases the expression of Lysine-specific demethylase 3B (KDM3B).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Lysine-specific demethylase 3B (KDM3B).	[23]

References

• [1] KDM3B shows tumor-suppressive activity and transcriptionally regulates HOXA1 through retinoic acid response elements in acute myeloid leukemia.Leuk Lymphoma. 2018 Jan;59(1):204-213. doi: 10.1080/10428194.2017.1324156. Epub 2017 May 25.
• [2] KDM3B is the H3K9 demethylase involved in transcriptional activation of lmo2 in leukemia.Mol Cell Biol. 2012 Jul;32(14):2917-33. doi: 10.1128/MCB.00133-12. Epub 2012 May 21.
• [3] KDM3B suppresses APL progression by restricting chromatin accessibility and facilitating the ATRA-mediated degradation of PML/RAR.Cancer Cell Int. 2019 Oct 4;19:256. doi: 10.1186/s12935-019-0979-7. eCollection 2019.
• [4] An epigenetic role for PRL-3 as a regulator of H3K9 methylation in colorectal cancer.Gut. 2013 Apr;62(4):571-81. doi: 10.1136/gutjnl-2011-301059. Epub 2012 Feb 16.
• [5] De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism. Am J Hum Genet. 2019 Apr 4;104(4):758-766. doi: 10.1016/j.ajhg.2019.02.023. Epub 2019 Mar 28.
• [6] Histone demethylase KDM3B regulates the transcriptional network of cell-cycle genes in hepatocarcinoma HepG2 cells.Biochem Biophys Res Commun. 2019 Jan 8;508(2):576-582. doi: 10.1016/j.bbrc.2018.11.179. Epub 2018 Dec 1.
• [7] A novel nuclear protein, 5qNCA (LOC51780) is a candidate for the myeloid leukemia tumor suppressor gene on chromosome 5 band q31.Oncogene. 2001 Oct 18;20(47):6946-54. doi: 10.1038/sj.onc.1204850.
• [8] Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.Mol Autism. 2017 May 22;8:21. doi: 10.1186/s13229-017-0137-9. eCollection 2017.
• [9] [Olygopeptide KND as a putative endogenous prototype of delta sleep inducing peptide (DSIP). Comparative study of biological properties].Bioorg Khim. 2013 May-Jun;39(3):277-84. doi: 10.1134/s1068162013030096.
• [10] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [11] Histone lysine demethylases in breast cancer.Crit Rev Oncol Hematol. 2013 May;86(2):97-103. doi: 10.1016/j.critrevonc.2012.11.008. Epub 2012 Dec 23.
• [12] Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer.Oncogene. 2020 Mar;39(10):2187-2201. doi: 10.1038/s41388-019-1116-8. Epub 2019 Dec 10.
• [13] Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.EBioMedicine. 2016 Aug;10:150-63. doi: 10.1016/j.ebiom.2016.07.022. Epub 2016 Jul 20.
• [14] 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.
• [15] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. J Biol Chem. 2013 May 31;288(22):16004-15. doi: 10.1074/jbc.M112.432294. Epub 2013 Apr 1.
• [20] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [21] 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.
• [22] 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.
• [23] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.