Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1VGYCX)

• DOT Name: Lysine-specific demethylase 7A (KDM7A)
• Synonyms: JmjC domain-containing histone demethylation protein 1D; Lysine-specific demethylase 7; -dimethyl-L-lysine9 demethylase 7A; EC 1.14.11.65
• Gene Name: KDM7A
• UniProt ID: KDM7A_HUMAN
• PDB ID: 3KV5; 3KV6; 3KV9; 3KVA; 3KVB; 3U78
• EC Number: 1.14.11.65
• Pfam ID: PF17811 ; PF02373 ; PF00628
• Sequence:
  MAGAAAAVAAGAAAGAAAAAVSVAAPGRASAPPPPPPVYCVCRQPYDVNRFMIECDICKD
  WFHGSCVGVEEHHAVDIDLYHCPNCAVLHGSSLMKKRRNWHRHDYTEIDDGSKPVQAGTR
  TFIKELRSRVFPSADEIIIKMHGSQLTQRYLEKHGFDVPIMVPKLDDLGLRLPSPTFSVM
  DVERYVGGDKVIDVIDVARQADSKMTLHNYVKYFMNPNRPKVLNVISLEFSDTKMSELVE
  VPDIAKKLSWVENYWPDDSVFPKPFVQKYCLMGVQDSYTDFHIDFGGTSVWYHVLWGEKI
  FYLIKPTDENLARYESWSSSVTQSEVFFGDKVDKCYKCVVKQGHTLFVPTGWIHAVLTSQ
  DCMAFGGNFLHNLNIGMQLRCYEMEKRLKTPDLFKFPFFEAICWFVAKNLLETLKELRED
  GFQPQTYLVQGVKALHTALKLWMKKELVSEHAFEIPDNVRPGHLIKELSKVIRAIEEENG
  KPVKSQGIPIVCPVSRSSNEATSPYHSRRKMRKLRDHNVRTPSNLDILELHTREVLKRLE
  MCPWEEDILSSKLNGKFNKHLQPSSTVPEWRAKDNDLRLLLTNGRIIKDERQPFADQSLY
  TADSENEEDKRRTKKAKMKIEESSGVEGVEHEESQKPLNGFFTRVKSELRSRSSGYSDIS
  ESEDSGPECTALKSIFTTEESESSGDEKKQEITSNFKEESNVMRNFLQKSQKPSRSEIPI
  KRECPTSTSTEEEAIQGMLSMAGLHYSTCLQRQIQSTDCSGERNSLQDPSSCHGSNHEVR
  QLYRYDKPVECGYHVKTEDPDLRTSSWIKQFDTSRFHPQDLSRSQKCIRKEGSSEISQRV
  QSRNYVDSSGSSLQNGKYMQNSNLTSGACQISNGSLSPERPVGETSFSVPLHPTKRPASN
  PPPISNQATKGKRPKKGMATAKQRLGKILKLNRNGHARFFV
• Function: Histone demethylase required for brain development. Specifically demethylates dimethylated 'Lys-9', 'Lys-27' and 'Lys-36' (H3K9me2, H3K27me2, H3K36me2, respectively) of histone H3 and monomethylated histone H4 'Lys-20' residue (H4K20Me1), thereby playing a central role in histone code. Specifically binds trimethylated 'Lys-4' of histone H3 (H3K4me3), affecting histone demethylase specificity: in presence of H3K4me3, it has no demethylase activity toward H3K9me2, while it has high activity toward H3K27me2. Demethylates H3K9me2 in absence of H3K4me3. Has activity toward H4K20Me1 only when nucleosome is used as a substrate and when not histone octamer is used as substrate.
• Reactome Pathway:
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  HDMs demethylate histones (R-HSA-3214842)
• BioCyc Pathway: MetaCyc:ENSG00000006459-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 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 7A (KDM7A).	[1]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Lysine-specific demethylase 7A (KDM7A).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Lysine-specific demethylase 7A (KDM7A).	[18]

17 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 7A (KDM7A).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lysine-specific demethylase 7A (KDM7A).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Lysine-specific demethylase 7A (KDM7A).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysine-specific demethylase 7A (KDM7A).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Lysine-specific demethylase 7A (KDM7A).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Lysine-specific demethylase 7A (KDM7A).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Lysine-specific demethylase 7A (KDM7A).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Lysine-specific demethylase 7A (KDM7A).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Lysine-specific demethylase 7A (KDM7A).	[10]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Lysine-specific demethylase 7A (KDM7A).	[11]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide increases the expression of Lysine-specific demethylase 7A (KDM7A).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Lysine-specific demethylase 7A (KDM7A).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Lysine-specific demethylase 7A (KDM7A).	[2]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Lysine-specific demethylase 7A (KDM7A).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Lysine-specific demethylase 7A (KDM7A).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lysine-specific demethylase 7A (KDM7A).	[17]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Lysine-specific demethylase 7A (KDM7A).	[19]

References

• [1] 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.
• [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] 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.
• [4] 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.
• [5] 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.
• [6] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [7] 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.
• [8] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [9] 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.
• [10] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [11] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [12] 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.
• [13] 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.
• [14] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] 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.
• [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] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.