Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRKL6YC)

• DOT Name: Chromodomain-helicase-DNA-binding protein 2 (CHD2)
• Synonyms: CHD-2; EC 3.6.4.12; ATP-dependent helicase CHD2
• Gene Name: CHD2
• Related Disease:
  Complex neurodevelopmental disorder
  Epilepsy
  Neoplasm
  Nervous system disease
  Autism spectrum disorder
  CHARGE syndrome
  Childhood epilepsy with centrotemporal spikes
  Congenital diaphragmatic hernia
  Dementia
  Developmental and epileptic encephalopathy 94
  Dravet syndrome
  Epithelial ovarian cancer
  Intellectual disability
  Neurodevelopmental disorder
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Small lymphocytic lymphoma
  Tourette syndrome
  West syndrome
  Advanced cancer
  Leukopenia
  Severe congenital neutropenia
  LennoxGastaut syndrome
  Myoclonic-astatic epilepsy
  Pervasive developmental disorder
• UniProt ID: CHD2_HUMAN
• EC Number: 3.6.4.12
• Pfam ID: PF18375 ; PF13907 ; PF00385 ; PF00271 ; PF00176
• Sequence:
  MMRNKDKSQEEDSSLHSNASSHSASEEASGSDSGSQSESEQGSDPGSGHGSESNSSSESS
  ESQSESESESAGSKSQPVLPEAKEKPASKKERIADVKKMWEEYPDVYGVRRSNRSRQEPS
  RFNIKEEASSGSESGSPKRRGQRQLKKQEKWKQEPSEDEQEQGTSAESEPEQKKVKARRP
  VPRRTVPKPRVKKQPKTQRGKRKKQDSSDEDDDDDEAPKRQTRRRAAKNVSYKEDDDFET
  DSDDLIEMTGEGVDEQQDNSETIEKVLDSRLGKKGATGASTTVYAIEANGDPSGDFDTEK
  DEGEIQYLIKWKGWSYIHSTWESEESLQQQKVKGLKKLENFKKKEDEIKQWLGKVSPEDV
  EYFNCQQELASELNKQYQIVERVIAVKTSKSTLGQTDFPAHSRKPAPSNEPEYLCKWMGL
  PYSECSWEDEALIGKKFQNCIDSFHSRNNSKTIPTRECKALKQRPRFVALKKQPAYLGGE
  NLELRDYQLEGLNWLAHSWCKNNSVILADEMGLGKTIQTISFLSYLFHQHQLYGPFLIVV
  PLSTLTSWQREFEIWAPEINVVVYIGDLMSRNTIREYEWIHSQTKRLKFNALITTYEILL
  KDKTVLGSINWAFLGVDEAHRLKNDDSLLYKTLIDFKSNHRLLITGTPLQNSLKELWSLL
  HFIMPEKFEFWEDFEEDHGKGRENGYQSLHKVLEPFLLRRVKKDVEKSLPAKVEQILRVE
  MSALQKQYYKWILTRNYKALAKGTRGSTSGFLNIVMELKKCCNHCYLIKPPEENERENGQ
  EILLSLIRSSGKLILLDKLLTRLRERGNRVLIFSQMVRMLDILAEYLTIKHYPFQRLDGS
  IKGEIRKQALDHFNADGSEDFCFLLSTRAGGLGINLASADTVVIFDSDWNPQNDLQAQAR
  AHRIGQKKQVNIYRLVTKGTVEEEIIERAKKKMVLDHLVIQRMDTTGRTILENNSGRSNS
  NPFNKEELTAILKFGAEDLFKELEGEESEPQEMDIDEILRLAETRENEVSTSATDELLSQ
  FKVANFATMEDEEELEERPHKDWDEIIPEEQRKKVEEEERQKELEEIYMLPRIRSSTKKA
  QTNDSDSDTESKRQAQRSSASESETEDSDDDKKPKRRGRPRSVRKDLVEGFTDAEIRRFI
  KAYKKFGLPLERLECIARDAELVDKSVADLKRLGELIHNSCVSAMQEYEEQLKENASEGK
  GPGKRRGPTIKISGVQVNVKSIIQHEEEFEMLHKSIPVDPEEKKKYCLTCRVKAAHFDVE
  WGVEDDSRLLLGIYEHGYGNWELIKTDPELKLTDKILPVETDKKPQGKQLQTRADYLLKL
  LRKGLEKKGAVTGGEEAKLKKRKPRVKKENKVPRLKEEHGIELSSPRHSDNPSEEGEVKD
  DGLEKSPMKKKQKKKENKENKEKQMSSRKDKEGDKERKKSKDKKEKPKSGDAKSSSKSKR
  SQGPVHITAGSEPVPIGEDEDDDLDQETFSICKERMRPVKKALKQLDKPDKGLNVQEQLE
  HTRNCLLKIGDRIAECLKAYSDQEHIKLWRRNLWIFVSKFTEFDARKLHKLYKMAHKKRS
  QEEEEQKKKDDVTGGKKPFRPEASGSSRDSLISQSHTSHNLHPQKPHLPASHGPQMHGHP
  RDNYNHPNKRHFSNADRGDWQRERKFNYGGGNNNPPWGSDRHHQYEQHWYKDHHYGDRRH
  MDAHRSGSYRPNNMSRKRPYDQYSSDRDHRGHRDYYDRHHHDSKRRRSDEFRPQNYHQQD
  FRRMSDHRPAMGYHGQGPSDHYRSFHTDKLGEYKQPLPPLHPAVSDPRSPPSQKSPHDSK
  SPLDHRSPLERSLEQKNNPDYNWNVRKT
• Function: DNA-binding helicase that specifically binds to the promoter of target genes, leading to chromatin remodeling, possibly by promoting deposition of histone H3.3. Involved in myogenesis via interaction with MYOD1: binds to myogenic gene regulatory sequences and mediates incorporation of histone H3.3 prior to the onset of myogenic gene expression, promoting their expression.

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Epilepsy	DISBB28L	Definitive	Genetic Variation	[2]
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[3]
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[4]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[5]
CHARGE syndrome	DISKD3CW	Strong	Biomarker	[6]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Strong	CausalMutation	[7]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Biomarker	[8]
Dementia	DISXL1WY	Strong	Biomarker	[9]
Developmental and epileptic encephalopathy 94	DISK16WB	Strong	Autosomal dominant	[10]
Dravet syndrome	DISJF7LY	Strong	Genetic Variation	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[13]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[14]
Obesity	DIS47Y1K	Strong	Genetic Variation	[15]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[12]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[16]
Tourette syndrome	DISX9D54	Strong	Biomarker	[17]
West syndrome	DISLIAU9	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[18]
Leukopenia	DISJMBMM	moderate	Biomarker	[19]
Severe congenital neutropenia	DISES99N	moderate	Genetic Variation	[19]
LennoxGastaut syndrome	DISOTGO5	Supportive	Autosomal dominant	[10]
Myoclonic-astatic epilepsy	DISTAVMU	Supportive	Unknown	[10]
Pervasive developmental disorder	DIS51975	Limited	Genetic Variation	[20]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Chromodomain-helicase-DNA-binding protein 2 (CHD2) affects the response to substance of Temozolomide.	[41]
DTI-015	DMXZRW0	Approved	Chromodomain-helicase-DNA-binding protein 2 (CHD2) affects the response to substance of DTI-015.	[41]

6 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 Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the methylation of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[33]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[35]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[37]

14 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 Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[23]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[24]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[27]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[28]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[29]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[30]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[31]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[32]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[38]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[39]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Chromodomain-helicase-DNA-binding protein 2 (CHD2).	[40]

References

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• [2] CHD2-related epilepsy: novel mutations and new phenotypes.Dev Med Child Neurol. 2020 May;62(5):647-653. doi: 10.1111/dmcn.14367. Epub 2019 Nov 1.
• [3] Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL.Blood. 2020 Jan 30;135(5):360-370. doi: 10.1182/blood.2019001904.
• [4] Regulation of CHD2 expression by the Chaserr long noncoding RNA gene is essential for viability.Nat Commun. 2019 Nov 8;10(1):5092. doi: 10.1038/s41467-019-13075-8.
• [5] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [6] Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency.Eur J Med Genet. 2012 Feb;55(2):132-4. doi: 10.1016/j.ejmg.2011.10.004. Epub 2011 Nov 25.
• [7] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [8] Congenital diaphragmatic hernia and chromosome 15q26: determination of a candidate region by use of fluorescent in situ hybridization and array-based comparative genomic hybridization.Am J Hum Genet. 2005 May;76(5):877-82. doi: 10.1086/429842. Epub 2005 Mar 4.
• [9] Mutation Screening of the CHCHD2 Gene for Alzheimer's Disease and Frontotemporal Dementia in Chinese Mainland Population.J Alzheimers Dis. 2018;61(4):1283-1288. doi: 10.3233/JAD-170692.
• [10] Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013 Jul;45(7):825-30. doi: 10.1038/ng.2646. Epub 2013 May 26.
• [11] De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome.Am J Hum Genet. 2013 Nov 7;93(5):967-75. doi: 10.1016/j.ajhg.2013.09.017. Epub 2013 Oct 24.
• [12] CircRNA UBAP2 promotes the progression of ovarian cancer by sponging microRNA-144.Eur Rev Med Pharmacol Sci. 2019 Sep;23(17):7283-7294. doi: 10.26355/eurrev_201909_18833.
• [13] Autism-linked CHD gene expression patterns during development predict multi-organ disease phenotypes.J Anat. 2018 Dec;233(6):755-769. doi: 10.1111/joa.12889. Epub 2018 Oct 2.
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• [16] A Quantitative Analysis of Subclonal and Clonal Gene Mutations before and after Therapy in Chronic Lymphocytic Leukemia.Clin Cancer Res. 2016 Sep 1;22(17):4525-35. doi: 10.1158/1078-0432.CCR-15-3103. Epub 2016 Apr 8.
• [17] CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4468-77. doi: 10.1073/pnas.1405266111. Epub 2014 Oct 7.
• [18] Mutations in CHD2 cause defective association with active chromatin in chronic lymphocytic leukemia.Blood. 2015 Jul 9;126(2):195-202. doi: 10.1182/blood-2014-10-604959. Epub 2015 Jun 1.
• [19] Application of whole-exome sequencing to unravel the molecular basis of undiagnosed syndromic congenital neutropenia with intellectual disability.Am J Med Genet A. 2017 Jan;173(1):62-71. doi: 10.1002/ajmg.a.37969. Epub 2016 Sep 12.
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• [21] 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.
• [22] 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.
• [23] 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.
• [24] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [25] 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.
• [26] Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic. Oncotarget. 2015 Aug 28;6(25):21493-506. doi: 10.18632/oncotarget.4085.
• [27] 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.
• [28] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
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• [30] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [31] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [32] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [33] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [34] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [35] 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.
• [36] 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.
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• [39] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [40] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [41] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.