Details of Drug Off-Target (DOT)

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

• DOT Name: Chromodomain-helicase-DNA-binding protein 4 (CHD4)
• Synonyms: CHD-4; EC 3.6.4.12; ATP-dependent helicase CHD4; Mi-2 autoantigen 218 kDa protein; Mi2-beta
• Gene Name: CHD4
• Related Disease:
  Autism spectrum disorder
  Syndromic intellectual disability
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Adult glioblastoma
  Autism
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Colorectal carcinoma
  Constipation
  Endometrial carcinoma
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Idiopathic inflammatory myopathy
  Intellectual disability
  Liver cancer
  Lung adenocarcinoma
  Malignant peripheral nerve sheath tumor
  Megalencephaly
  Metastatic malignant neoplasm
  Schizophrenia
  Sifrim-Hitz-Weiss syndrome
  Small-cell lung cancer
  Triple negative breast cancer
  Neoplasm
  Advanced cancer
  Connective tissue disorder
  Endometrial cancer
  Endometrium neoplasm
  Neurodevelopmental disorder
  Rectal carcinoma
• UniProt ID: CHD4_HUMAN
• PDB ID: 1MM2; 1MM3; 2EE1; 2L5U; 2L75; 2N5N; 4O9I; 6BGG; 6Q3M; 6RYR; 6RYU; 8D4Y
• EC Number: 3.6.4.12
• Pfam ID: PF08074 ; PF06461 ; PF08073 ; PF00385 ; PF06465 ; PF00271 ; PF00628 ; PF00176
• Sequence:
  MASGLGSPSPCSAGSEEEDMDALLNNSLPPPHPENEEDPEEDLSETETPKLKKKKKPKKP
  RDPKIPKSKRQKKERMLLCRQLGDSSGEGPEFVEEEEEVALRSDSEGSDYTPGKKKKKKL
  GPKKEKKSKSKRKEEEEEEDDDDDSKEPKSSAQLLEDWGMEDIDHVFSEEDYRTLTNYKA
  FSQFVRPLIAAKNPKIAVSKMMMVLGAKWREFSTNNPFKGSSGASVAAAAAAAVAVVESM
  VTATEVAPPPPPVEVPIRKAKTKEGKGPNARRKPKGSPRVPDAKKPKPKKVAPLKIKLGG
  FGSKRKRSSSEDDDLDVESDFDDASINSYSVSDGSTSRSSRSRKKLRTTKKKKKGEEEVT
  AVDGYETDHQDYCEVCQQGGEIILCDTCPRAYHMVCLDPDMEKAPEGKWSCPHCEKEGIQ
  WEAKEDNSEGEEILEEVGGDLEEEDDHHMEFCRVCKDGGELLCCDTCPSSYHIHCLNPPL
  PEIPNGEWLCPRCTCPALKGKVQKILIWKWGQPPSPTPVPRPPDADPNTPSPKPLEGRPE
  RQFFVKWQGMSYWHCSWVSELQLELHCQVMFRNYQRKNDMDEPPSGDFGGDEEKSRKRKN
  KDPKFAEMEERFYRYGIKPEWMMIHRILNHSVDKKGHVHYLIKWRDLPYDQASWESEDVE
  IQDYDLFKQSYWNHRELMRGEEGRPGKKLKKVKLRKLERPPETPTVDPTVKYERQPEYLD
  ATGGTLHPYQMEGLNWLRFSWAQGTDTILADEMGLGKTVQTAVFLYSLYKEGHSKGPFLV
  SAPLSTIINWEREFEMWAPDMYVVTYVGDKDSRAIIRENEFSFEDNAIRGGKKASRMKKE
  ASVKFHVLLTSYELITIDMAILGSIDWACLIVDEAHRLKNNQSKFFRVLNGYSLQHKLLL
  TGTPLQNNLEELFHLLNFLTPERFHNLEGFLEEFADIAKEDQIKKLHDMLGPHMLRRLKA
  DVFKNMPSKTELIVRVELSPMQKKYYKYILTRNFEALNARGGGNQVSLLNVVMDLKKCCN
  HPYLFPVAAMEAPKMPNGMYDGSALIRASGKLLLLQKMLKNLKEGGHRVLIFSQMTKMLD
  LLEDFLEHEGYKYERIDGGITGNMRQEAIDRFNAPGAQQFCFLLSTRAGGLGINLATADT
  VIIYDSDWNPHNDIQAFSRAHRIGQNKKVMIYRFVTRASVEERITQVAKKKMMLTHLVVR
  PGLGSKTGSMSKQELDDILKFGTEELFKDEATDGGGDNKEGEDSSVIHYDDKAIERLLDR
  NQDETEDTELQGMNEYLSSFKVAQYVVREEEMGEEEEVEREIIKQEESVDPDYWEKLLRH
  HYEQQQEDLARNLGKGKRIRKQVNYNDGSQEDRDWQDDQSDNQSDYSVASEEGDEDFDER
  SEAPRRPSRKGLRNDKDKPLPPLLARVGGNIEVLGFNARQRKAFLNAIMRYGMPPQDAFT
  TQWLVRDLRGKSEKEFKAYVSLFMRHLCEPGADGAETFADGVPREGLSRQHVLTRIGVMS
  LIRKKVQEFEHVNGRWSMPELAEVEENKKMSQPGSPSPKTPTPSTPGDTQPNTPAPVPPA
  EDGIKIEENSLKEEESIEGEKEVKSTAPETAIECTQAPAPASEDEKVVVEPPEGEEKVEK
  AEVKERTEEPMETEPKGAADVEKVEEKSAIDLTPIVVEDKEEKKEEEEKKEVMLQNGETP
  KDLNDEKQKKNIKQRFMFNIADGGFTELHSLWQNEERAATVTKKTYEIWHRRHDYWLLAG
  IINHGYARWQDIQNDPRYAILNEPFKGEMNRGNFLEIKNKFLARRFKLLEQALVIEEQLR
  RAAYLNMSEDPSHPSMALNTRFAEVECLAESHQHLSKESMAGNKPANAVLHKVLKQLEEL
  LSDMKADVTRLPATIARIPPVAVRLQMSERNILSRLANRAPEPTPQQVAQQQ
• Function: ATP-dependent helicase that binds and distorts nucleosomal DNA. Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin. Localizes to acetylated damaged chromatin in a ZMYND8-dependent manner, to promote transcriptional repression and double-strand break repair by homologous recombination. Involved in neurogenesis.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Human papillomavirus infection (hsa05165)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (R-HSA-427389)
  Regulation of TP53 Activity through Acetylation (R-HSA-6804758)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  NGF-stimulated transcription (R-HSA-9031628)
  Potential therapeutics for SARS (R-HSA-9679191)
  HDACs deacetylate histones (R-HSA-3214815)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Definitive	Biomarker	[1]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[2]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Autism	DISV4V1Z	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Constipation	DISRQXWI	Strong	Genetic Variation	[10]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[11]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Biomarker	[13]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[14]
Liver cancer	DISDE4BI	Strong	Biomarker	[8]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[15]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Biomarker	[16]
Megalencephaly	DISYW5SV	Strong	Genetic Variation	[14]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[9]
Schizophrenia	DISSRV2N	Strong	Biomarker	[17]
Sifrim-Hitz-Weiss syndrome	DISCITSF	Strong	Autosomal dominant	[18]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[19]
Triple negative breast cancer	DISAMG6N	moderate	Biomarker	[20]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[21]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[4]
Connective tissue disorder	DISKXBS3	Limited	Biomarker	[22]
Endometrial cancer	DISW0LMR	Limited	Genetic Variation	[11]
Endometrium neoplasm	DIS6OS2L	Limited	Biomarker	[23]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[24]
Rectal carcinoma	DIS8FRR7	Limited	Biomarker	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[28]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[29]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[30]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[31]
Selenium	DM25CGV	Approved	Selenium increases the expression of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[32]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[33]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[34]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[34]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[38]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[36]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[39]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[37]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the O-linked glycosylation of Chromodomain-helicase-DNA-binding protein 4 (CHD4).	[40]

References

• [1] Regulation of neuronal connectivity in the mammalian brain by chromatin remodeling.Curr Opin Neurobiol. 2019 Dec;59:59-68. doi: 10.1016/j.conb.2019.04.010. Epub 2019 May 28.
• [2] 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.
• [3] Depletion of the chromatin remodeler CHD4 sensitizes AML blasts to genotoxic agents and reduces tumor formation.Blood. 2015 Sep 17;126(12):1462-72. doi: 10.1182/blood-2015-03-631606. Epub 2015 Aug 11.
• [4] CHD4 regulates the DNA damage response and RAD51 expression in glioblastoma.Sci Rep. 2019 Mar 14;9(1):4444. doi: 10.1038/s41598-019-40327-w.
• [5] Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity.Nat Genet. 2019 Jan;51(1):106-116. doi: 10.1038/s41588-018-0288-4. Epub 2018 Dec 17.
• [6] The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2(+) breast cancer cells.Biol Open. 2019 Apr 18;8(4):bio038323. doi: 10.1242/bio.038323.
• [7] RNAi screens identify CHD4 as an essential gene in breast cancer growth.Oncotarget. 2016 Dec 6;7(49):80901-80915. doi: 10.18632/oncotarget.12646.
• [8] Defeating EpCAM(+) liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma.J Hepatol. 2015 Nov;63(5):1164-72. doi: 10.1016/j.jhep.2015.06.009. Epub 2015 Jun 18.
• [9] CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes.Cancer Cell. 2017 May 8;31(5):653-668.e7. doi: 10.1016/j.ccell.2017.04.005.
• [10] Treatment and Patient Reported Outcome in Children with Hirschsprung Disease and Concomitant Congenital Heart Disease.Biomed Res Int. 2017;2017:1703483. doi: 10.1155/2017/1703483. Epub 2017 Mar 8.
• [11] CHD4 mutations promote endometrial cancer stemness by activating TGF-beta signaling.Am J Cancer Res. 2018 May 1;8(5):903-914. eCollection 2018.
• [12] EZH2-, CHD4-, and IDH-linked epigenetic perturbation and its association with survival in glioma patients.J Mol Cell Biol. 2017 Dec 1;9(6):477-488. doi: 10.1093/jmcb/mjx056.
• [13] Autoantibodies to Mi-2 alpha and Mi-2 beta in patients with idiopathic inflammatory myopathy.Rheumatology (Oxford). 2019 Sep 1;58(9):1655-1661. doi: 10.1093/rheumatology/kez092.
• [14] The NuRD complex and macrocephaly associated neurodevelopmental disorders.Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):548-556. doi: 10.1002/ajmg.c.31752. Epub 2019 Nov 18.
• [15] Characteristics of genomic alterations of lung adenocarcinoma in young never-smokers.Int J Cancer. 2018 Oct 1;143(7):1696-1705. doi: 10.1002/ijc.31542. Epub 2018 May 7.
• [16] CHD4 as a Potential Biomarker in Differentiating Between Cellular Schwannoma and Malignant Peripheral Nerve Sheath Tumor.Appl Immunohistochem Mol Morphol. 2018 Nov/Dec;26(10):775-780. doi: 10.1097/PAI.0000000000000522.
• [17] Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet. 2011 Jul 10;43(9):860-3. doi: 10.1038/ng.886.
• [18] Constraint of gene expression by the chromatin remodelling protein CHD4 facilitates lineage specification. Development. 2015 Aug 1;142(15):2586-97. doi: 10.1242/dev.125450. Epub 2015 Jun 26.
• [19] Differential Proteomic Analysis between Small Cell Lung Carcinoma (SCLC) and Pulmonary Carcinoid Tumors Reveals Molecular Signatures for Malignancy in Lung Cancer.Proteomics Clin Appl. 2018 Nov;12(6):e1800015. doi: 10.1002/prca.201800015. Epub 2018 Jul 5.
• [20] Identification of CHD4-1 integrin axis as a prognostic marker in triple-negative breast cancer using next-generation sequencing and bioinformatics.Life Sci. 2019 Dec 1;238:116963. doi: 10.1016/j.lfs.2019.116963. Epub 2019 Oct 19.
• [21] Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy.Int J Mol Sci. 2019 Aug 21;20(17):4087. doi: 10.3390/ijms20174087.
• [22] Myositis-specific autoantibodies in dermatomyositis/polymyositis with interstitial lung disease.J Neurol Sci. 2019 Feb 15;397:123-128. doi: 10.1016/j.jns.2018.12.040. Epub 2018 Dec 31.
• [23] Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes.Nat Genet. 2012 Dec;44(12):1310-5. doi: 10.1038/ng.2455. Epub 2012 Oct 28.
• [24] The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.Genet Med. 2020 Feb;22(2):389-397. doi: 10.1038/s41436-019-0612-0. Epub 2019 Aug 7.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [32] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [33] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [34] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [35] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [36] 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.
• [37] 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.
• [38] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [39] 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.
• [40] O-Linked N-Acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Interact with Mi2 Protein at the A-Globin Promoter. J Biol Chem. 2016 Jul 22;291(30):15628-40. doi: 10.1074/jbc.M116.721928. Epub 2016 May 26.