Details of Drug Off-Target (DOT)

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

• DOT Name: Lysine-specific histone demethylase 2 (KDM1B)
• Synonyms: EC 1.14.99.66; Flavin-containing amine oxidase domain-containing protein 1; Lysine-specific histone demethylase 1B
• Gene Name: KDM1B
• UniProt ID: KDM1B_HUMAN
• PDB ID: 4FWE; 4FWF; 4FWJ; 4GU0; 4GU1; 4GUR; 4GUS; 4GUT; 4GUU; 4HSU; 6R1U; 6R25; 7XE1; 7XE2; 7XE3
• EC Number: 1.14.99.66
• Pfam ID: PF01593 ; PF04433 ; PF07496
• Sequence:
  MATPRGRTKKKASFDHSPDSLPLRSSGRQAKKKATETTDEDEDGGSEKKYRKCEKAGCTA
  TCPVCFASASERCAKNGYTSRWYHLSCGEHFCNECFDHYYRSHKDGYDKYTTWKKIWTSN
  GKTEPSPKAFMADQQLPYWVQCTKPECRKWRQLTKEIQLTPQIAKTYRCGMKPNTAIKPE
  TSDHCSLPEDLRVLEVSNHWWYSMLILPPLLKDSVAAPLLSAYYPDCVGMSPSCTSTNRA
  AATGNASPGKLEHSKAALSVHVPGMNRYFQPFYQPNECGKALCVRPDVMELDELYEFPEY
  SRDPTMYLALRNLILALWYTNCKEALTPQKCIPHIIVRGLVRIRCVQEVERILYFMTRKG
  LINTGVLSVGADQYLLPKDYHNKSVIIIGAGPAGLAAARQLHNFGIKVTVLEAKDRIGGR
  VWDDKSFKGVTVGRGAQIVNGCINNPVALMCEQLGISMHKFGERCDLIQEGGRITDPTID
  KRMDFHFNALLDVVSEWRKDKTQLQDVPLGEKIEEIYKAFIKESGIQFSELEGQVLQFHL
  SNLEYACGSNLHQVSARSWDHNEFFAQFAGDHTLLTPGYSVIIEKLAEGLDIQLKSPVQC
  IDYSGDEVQVTTTDGTGYSAQKVLVTVPLALLQKGAIQFNPPLSEKKMKAINSLGAGIIE
  KIALQFPYRFWDSKVQGADFFGHVPPSASKRGLFAVFYDMDPQKKHSVLMSVIAGEAVAS
  VRTLDDKQVLQQCMATLRELFKEQEVPDPTKYFVTRWSTDPWIQMAYSFVKTGGSGEAYD
  IIAEDIQGTVFFAGEATNRHFPQTVTGAYLSGVREASKIAAF
• Function: Histone demethylase that demethylates 'Lys-4' of histone H3, a specific tag for epigenetic transcriptional activation, thereby acting as a corepressor. Required for de novo DNA methylation of a subset of imprinted genes during oogenesis. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Demethylates both mono- and di-methylated 'Lys-4' of histone H3. Has no effect on tri-methylated 'Lys-4', mono-, di- or tri-methylated 'Lys-9', mono-, di- or tri-methylated 'Lys-27', mono-, di- or tri-methylated 'Lys-36' of histone H3, or on mono-, di- or tri-methylated 'Lys-20' of histone H4. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of GLYR1 to achieve such activity, they form a multifunctional enzyme complex that modifies transcribed chromatin and facilitates Pol II transcription through nucleosomes.
• Reactome Pathway:
  UCH proteinases (R-HSA-5689603)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  HDMs demethylate histones (R-HSA-3214842)
• BioCyc Pathway: MetaCyc:ENSG00000165097-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Lysine-specific histone demethylase 2 (KDM1B).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Lysine-specific histone demethylase 2 (KDM1B).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Lysine-specific histone demethylase 2 (KDM1B).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysine-specific histone demethylase 2 (KDM1B).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Lysine-specific histone demethylase 2 (KDM1B).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Lysine-specific histone demethylase 2 (KDM1B).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Lysine-specific histone demethylase 2 (KDM1B).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Lysine-specific histone demethylase 2 (KDM1B).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lysine-specific histone demethylase 2 (KDM1B).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Lysine-specific histone demethylase 2 (KDM1B).	[10]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Lysine-specific histone demethylase 2 (KDM1B).	[11]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Lysine-specific histone demethylase 2 (KDM1B).	[12]

References

• [1] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [9] 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.
• [10] 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.
• [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] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.