Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5DL94T)

• DOT Name: Lysine-specific demethylase 5B (KDM5B)
• Synonyms: EC 1.14.11.67; Cancer/testis antigen 31; CT31; Histone demethylase JARID1B; Jumonji/ARID domain-containing protein 1B; PLU-1; Retinoblastoma-binding protein 2 homolog 1; RBP2-H1; -trimethyl-L-lysine(4) demethylase 5B
• Gene Name: KDM5B
• Related Disease:
  Autism
  Intellectual disability, autosomal recessive 65
  Intellectual disability
  Autosomal recessive non-syndromic intellectual disability
  Tourette syndrome
• UniProt ID: KDM5B_HUMAN
• PDB ID: 2MA5 ; 2MNY ; 2MNZ ; 5A1F ; 5A3N ; 5A3P ; 5A3T ; 5A3W ; 5FPL ; 5FPU ; 5FUN ; 5FUP ; 5FV3 ; 5FY4 ; 5FY5 ; 5FY9 ; 5FYB ; 5FYS ; 5FYT ; 5FYU ; 5FYV ; 5FYY ; 5FYZ ; 5FZ0 ; 5FZ1 ; 5FZ3 ; 5FZ4 ; 5FZ6 ; 5FZ7 ; 5FZ8 ; 5FZ9 ; 5FZA ; 5FZB ; 5FZC ; 5FZD ; 5FZE ; 5FZF ; 5FZG ; 5FZH ; 5FZI ; 5FZK ; 5FZL ; 5FZM ; 5LW9 ; 5LWB ; 6EIN ; 6EIU ; 6EIY ; 6EJ0 ; 6EJ1 ; 6EK6 ; 6H4Z ; 6H50 ; 6H51 ; 6H52 ; 6RBI
• EC Number: 1.14.11.67
• Pfam ID: PF01388 ; PF02373 ; PF02375 ; PF21323 ; PF00628 ; PF08429 ; PF02928
• Sequence:
  MEAATTLHPGPRPALPLGGPGPLGEFLPPPECPVFEPSWEEFADPFAFIHKIRPIAEQTG
  ICKVRPPPDWQPPFACDVDKLHFTPRIQRLNELEAQTRVKLNFLDQIAKYWELQGSTLKI
  PHVERKILDLFQLNKLVAEEGGFAVVCKDRKWTKIATKMGFAPGKAVGSHIRGHYERILN
  PYNLFLSGDSLRCLQKPNLTTDTKDKEYKPHDIPQRQSVQPSETCPPARRAKRMRAEAMN
  IKIEPEETTEARTHNLRRRMGCPTPKCENEKEMKSSIKQEPIERKDYIVENEKEKPKSRS
  KKATNAVDLYVCLLCGSGNDEDRLLLCDGCDDSYHTFCLIPPLHDVPKGDWRCPKCLAQE
  CSKPQEAFGFEQAARDYTLRTFGEMADAFKSDYFNMPVHMVPTELVEKEFWRLVSTIEED
  VTVEYGADIASKEFGSGFPVRDGKIKLSPEEEEYLDSGWNLNNMPVMEQSVLAHITADIC
  GMKLPWLYVGMCFSSFCWHIEDHWSYSINYLHWGEPKTWYGVPGYAAEQLENVMKKLAPE
  LFVSQPDLLHQLVTIMNPNTLMTHEVPVYRTNQCAGEFVITFPRAYHSGFNQGFNFAEAV
  NFCTVDWLPLGRQCVEHYRLLHRYCVFSHDEMICKMASKADVLDVVVASTVQKDMAIMIE
  DEKALRETVRKLGVIDSERMDFELLPDDERQCVKCKTTCFMSAISCSCKPGLLVCLHHVK
  ELCSCPPYKYKLRYRYTLDDLYPMMNALKLRAESYNEWALNVNEALEAKINKKKSLVSFK
  ALIEESEMKKFPDNDLLRHLRLVTQDAEKCASVAQQLLNGKRQTRYRSGGGKSQNQLTVN
  ELRQFVTQLYALPCVLSQTPLLKDLLNRVEDFQQHSQKLLSEETPSAAELQDLLDVSFEF
  DVELPQLAEMRIRLEQARWLEEVQQACLDPSSLTLDDMRRLIDLGVGLAPYSAVEKAMAR
  LQELLTVSEHWDDKAKSLLKARPRHSLNSLATAVKEIEEIPAYLPNGAALKDSVQRARDW
  LQDVEGLQAGGRVPVLDTLIELVTRGRSIPVHLNSLPRLETLVAEVQAWKECAVNTFLTE
  NSPYSLLEVLCPRCDIGLLGLKRKQRKLKEPLPNGKKKSTKLESLSDLERALTESKETAS
  AMATLGEARLREMEALQSLRLANEGKLLSPLQDVDIKICLCQKAPAAPMIQCELCRDAFH
  TSCVAVPSISQGLRIWLCPHCRRSEKPPLEKILPLLASLQRIRVRLPEGDALRYMIERTV
  NWQHRAQQLLSSGNLKFVQDRVGSGLLYSRWQASAGQVSDTNKVSQPPGTTSFSLPDDWD
  NRTSYLHSPFSTGRSCIPLHGVSPEVNELLMEAQLLQVSLPEIQELYQTLLAKPSPAQQT
  DRSSPVRPSSEKNDCCRGKRDGINSLERKLKRRLEREGLSSERWERVKKMRTPKKKKIKL
  SHPKDMNNFKLERERSYELVRSAETHSLPSDTSYSEQEDSEDEDAICPAVSCLQPEGDEV
  DWVQCDGSCNQWFHQVCVGVSPEMAEKEDYICVRCTVKDAPSRK
• Function: Histone demethylase that demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9' or H3 'Lys-27'. Demethylates trimethylated, dimethylated and monomethylated H3 'Lys-4'. Acts as a transcriptional corepressor for FOXG1B and PAX9. Favors the proliferation of breast cancer cells by repressing tumor suppressor genes such as BRCA1 and HOXA5. In contrast, may act as a tumor suppressor for melanoma. Represses the CLOCK-BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2.
• Tissue Specificity: Ubiquitously expressed, with highest levels in testis. Down-regulated in melanoma and glioblastoma. Up-regulated in breast cancer (at protein level).
• Reactome Pathway:
  TFAP2 (AP-2) family regulates transcription of cell cycle factors (R-HSA-8866911)
  Chromatin modifications during the maternal to zygotic transition (MZT) (R-HSA-9821002)
  HDMs demethylate histones (R-HSA-3214842)
• BioCyc Pathway: MetaCyc:ENSG00000117139-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Autosomal dominant	[1]
Intellectual disability, autosomal recessive 65	DIS1VSKB	Strong	Autosomal recessive	[2]
Intellectual disability	DISMBNXP	Moderate	Autosomal recessive	[3]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[4]
Tourette syndrome	DISX9D54	No Known	Unknown	[5]

18 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 Lysine-specific demethylase 5B (KDM5B).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lysine-specific demethylase 5B (KDM5B).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lysine-specific demethylase 5B (KDM5B).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Lysine-specific demethylase 5B (KDM5B).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Lysine-specific demethylase 5B (KDM5B).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Lysine-specific demethylase 5B (KDM5B).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Lysine-specific demethylase 5B (KDM5B).	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Lysine-specific demethylase 5B (KDM5B).	[13]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Lysine-specific demethylase 5B (KDM5B).	[14]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Lysine-specific demethylase 5B (KDM5B).	[15]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Lysine-specific demethylase 5B (KDM5B).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Lysine-specific demethylase 5B (KDM5B).	[17]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Lysine-specific demethylase 5B (KDM5B).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Lysine-specific demethylase 5B (KDM5B).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Lysine-specific demethylase 5B (KDM5B).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Lysine-specific demethylase 5B (KDM5B).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Lysine-specific demethylase 5B (KDM5B).	[23]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Lysine-specific demethylase 5B (KDM5B).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Lysine-specific demethylase 5B (KDM5B).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of Lysine-specific demethylase 5B (KDM5B).	[21]

References

• [1] Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017 Feb 23;542(7642):433-438. doi: 10.1038/nature21062. Epub 2017 Jan 25.
• [2] The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3. PLoS Genet. 2013 Apr;9(4):e1003461. doi: 10.1371/journal.pgen.1003461. Epub 2013 Apr 18.
• [3] 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.
• [4] Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders. Am J Hum Genet. 2018 Jan 4;102(1):175-187. doi: 10.1016/j.ajhg.2017.11.013. Epub 2017 Dec 21.
• [5] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] 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.
• [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] Alcohol triggered bile acid disequilibrium by suppressing BSEP to sustain hepatocellular carcinoma progression. Chem Biol Interact. 2022 Apr 1;356:109847. doi: 10.1016/j.cbi.2022.109847. Epub 2022 Feb 9.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] 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.
• [20] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [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] Global and region-specific post-transcriptional and post-translational modifications of bisphenol A in human prostate cancer cells. Environ Pollut. 2019 Dec;255(Pt 2):113318. doi: 10.1016/j.envpol.2019.113318. Epub 2019 Oct 2.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [24] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.