Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3P5HQD)

• DOT Name: Ectopic P granules protein 5 homolog (EPG5)
• Gene Name: EPG5
• Related Disease:
  Vici syndrome
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Breast cancer
  Breast carcinoma
  Cardiomyopathy
  Colorectal carcinoma
  Hypopigmentation of the skin
  Idiopathic cardiomyopathy
  Immunodeficiency
  Non-small-cell lung cancer
  Pneumonia
  Pneumonitis
  Sengers syndrome
  Neurodevelopmental disorder
  Corpus callosum, agenesis of
  Isolated congenital microcephaly
• UniProt ID: EPG5_HUMAN
• PDB ID: 7JHX
• Sequence:
  MAEAVKPQRRAKAKASRTKTKEKKKYETPQREESSEVSLPKTSREQEIPSLACEFKGDHL
  KVVTDSQLQDDASGQNESEMFDVPLTSLTISNEESLTCNTEPPKEGGEARPCVGDSAVTP
  KVHPGDNVGTKVETPKNFTEVEENMSVQGGLSESAPQSNFSYTQPAMENIQVRETQNSKE
  DKQGLVCSSEVPQNVGLQSSCPAKHGFQTPRVKKLYPQLPAEIAGEAPALVAVKPLLRSE
  RLYPELPSQLELVPFTKEQLKILEPGSWLENVESYLEEFDSMAHQDRHEFYELLLNYSRC
  RKQLLLAEAELLTLTSDCQNAKSRLWQFKEEQMSVQGICADQVKVFSYHRYQRVEMNENA
  LVELKKLFDAKSEHLHQTLALHSYTSVLSRLQVESYIYALLSSSAVLRSSAIHQQGRASK
  QTESIPSDLCQLKECISVLFMFTRRVNEDTQFHDDILLWLQKLVSVLQRVGCPGDHLFLL
  NHILRCPAGVSKWAVPFIQIKVLHNPSGVFHFMQSLALLMSPVKNRAEFMCHMKPSERKP
  SSSGPGSGTWTLVDEGGEEDEDPETSWILLNEDDLVTILAQFPFHELFQHLLGFKAKGDY
  LPETTRPQEMMKIFAFANSLVELLAVGLETFNRARYRQFVKRIGYMIRMTLGYVSDHWAQ
  YVSHNQGSGLAQQPYSMEKLQVEFDELFLRAVLHVLKAKRLGIWLFMSEMPFGTLSVQML
  WKLFYLMHQVESENLQQLSSSLQPAQCKQQLQDPEHFTNFEKCLSSMNSSEEICLLTTFA
  QMAQARRTNVDEDFIKIIVLEIYEVSYVTLSTRETFSKVGRELLGTITAVHPEIISVLLD
  RVQETIDQVGMVSLYLFKELPLYLWQPSASEIAVIRDWLLNYNLTVVKNKLACVILEGLN
  WGFAKQATLHLDQAVHAEVALMVLEAYQKYLAQKPYAGILSESMKQVSYLASIVRYGETP
  ETSFNQWAWNLILRLKLHKNDYGIQPNCPAVPFSVTVPDMTESPTFHPLLKAVKAGMPIG
  CYLALSMTAVGHSIEKFCAEGIPLLGILVQSRHLRTVVHVLDKILPLFYPCQYYLLKNEQ
  FLSHLLLFLHLDSGVPQGVTQQVTHKVAQHLTGASHGDNVKLLNSMIQAHISVSTQPNEV
  GPVAVLEFWVQALISQHLWYREQPILFLMDHLCKAAFQLMQEDCIQKLLYQQHKNALGYH
  CDRSLLSSLVSWIVAGNITPSFVEGLATPTQVWFAWTVLNMESIFEEDSQLRRVIEGELV
  INSAFTPDQALKKAQTQLKLPIVPSLQRLLIYRWAHQALVTPSDHPLLPLIWQKFFLLYL
  HRPGPQYGLPIDGCIGRRFFQSPAHINLLKEMKRRLTEVADFHHAASKALRVPAEGSEGL
  PESHSGTPGYLTSPELHKELVRLFNVYILWLEDENFQKGDTYIPSLPKHYDIHRLAKVMQ
  NQQDLWMEYLNMERIYHEFQETVGLWTQAKLESHSTPCSLSVQLDFTDPLLAKERVLSNL
  RKHEAPQPPLALHPTKPPVPVISSAVLLSQKDATQLVCTDLNLLQQQARTAALRESQQVA
  LDGELLDTMPKQYVNREEQTTLHLECRGSSGKKCQGAAVVTVQFEGMHKNEAISQQLHVL
  RKEVKQLQAEAAKPPSLNIVEAAVHAENLITALVNAYKLQPTPGIQKVGISLFFTIVDYV
  SDETQRHPPTRQFFTSCIEILGQVFISGIKSECRKVLETILKNSRLCSLLSPFFTPNAAP
  AEFIQLYEQVVKFLSEDNSDMIFMLLTKFDLKQWLSATKPPLSDRTRLLESIHLALTAWG
  LEPDEDILMPFNLFCKHWTYLLLYQFPDQYSDILRLLMQSSAEQLLSPECWKATLRALGC
  CAPSCQQGAASTEGAVLPSSSDALLSDKQVMETIQWLSDFFYKLRLSKMDFKSFGLFSKW
  SPYMADVKTFLGYLVKRLIDLEMTCLAQDPTASRKTVLKSLHSVIIQLFKPWILVLEDNE
  SSQQRHYPWLESDTVVASSIVQLFTDCIDSLHESFKDKLLPGDAGALWLHLMHYCEACTA
  PKMPEFILYAFHSTYRKLPWKDLHPDQMLMEAFFKVERGSPKSCFLFLGSVLCEVNWVSV
  LSDAWNSSPHPETRSMIVCLLFMMILLAKEVQLVDQTDSPLLSLLGQTSSLSWHLVDIVS
  YQSVLSYFSSHYPPSIILAKESYAELIMKLLKVSAGLSIPTDSQKHLDAVPKCQAFTHQM
  VQFLSTLEQNGKITLAVLEQEMSKLLDDIIVFNPPDMDSQTRHMALSSLFMEVLMMMNNA
  TIPTAEFLRGSIRTWIGQKMHGLVVLPLLTAACQSLASVRHMAETTEACITAYFKESPLN
  QNSGWGPILVSLQVPELTMEEFLQECLTLGSYLTLYVYLLQCLNSEQTLRNEMKVLLILS
  KWLEQVYPSSVEEEAKLFLWWHQVLQLSLIQTEQNDSVLTESVIRILLLVQSRQNLVAEE
  RLSSGILGAIGFGRKSPLSNRFRVVARSMAAFLSVQVPMEDQIRLRPGSELHLTPKAQQA
  LNALESMASSKQYVEYQDQILQATQFIRHPGHCLQDGKSFLALLVNCLYPEVHYLDHIR
• Function: Involved in autophagy. May play a role in a late step of autophagy, such as clearance of autophagosomal cargo. Plays a key role in innate and adaptive immune response triggered by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides from pathogens, and mediated by the nucleotide-sensing receptor TLR9. It is necessary for the translocation of CpG dinucleotides from early endosomes to late endosomes and lysosomes, where TLR9 is located.
• KEGG Pathway: Autophagy - animal (hsa04140)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Vici syndrome	DISSUIIM	Definitive	Autosomal recessive	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Hypopigmentation of the skin	DIS39YKC	Strong	Genetic Variation	[6]
Idiopathic cardiomyopathy	DISUGBZL	Strong	Biomarker	[7]
Immunodeficiency	DIS093I0	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Pneumonia	DIS8EF3M	Strong	Biomarker	[9]
Pneumonitis	DIS88E0K	Strong	Biomarker	[9]
Sengers syndrome	DISV24KG	Strong	Genetic Variation	[10]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[11]
Corpus callosum, agenesis of	DISO9P40	Limited	Biomarker	[12]
Isolated congenital microcephaly	DISUXHZ6	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ectopic P granules protein 5 homolog (EPG5).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ectopic P granules protein 5 homolog (EPG5).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ectopic P granules protein 5 homolog (EPG5).	[15]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Ectopic P granules protein 5 homolog (EPG5).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ectopic P granules protein 5 homolog (EPG5).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ectopic P granules protein 5 homolog (EPG5).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Ectopic P granules protein 5 homolog (EPG5).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ectopic P granules protein 5 homolog (EPG5).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ectopic P granules protein 5 homolog (EPG5).	[22]

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 Ectopic P granules protein 5 homolog (EPG5).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ectopic P granules protein 5 homolog (EPG5).	[19]

References

• [1] Agenesis of the corpus callosum, combined immunodeficiency, bilateral cataract, and hypopigmentation in two brothers. Am J Med Genet. 1988 Jan;29(1):1-8. doi: 10.1002/ajmg.1320290102.
• [2] Non-parametric Survival Analysis of EPG5 Gene with Age at Onset of Alzheimer's Disease.J Mol Neurosci. 2016 Dec;60(4):436-444. doi: 10.1007/s12031-016-0821-9. Epub 2016 Sep 1.
• [3] Mice deficient in Epg5 exhibit selective neuronal vulnerability to degeneration.J Cell Biol. 2013 Mar 18;200(6):731-41. doi: 10.1083/jcb.201211014. Epub 2013 Mar 11.
• [4] Comparative integromics on the breast cancer-associated gene KIAA1632: clues to a cancer antigen domain.Int J Oncol. 2007 Jul;31(1):205-10.
• [5] Autopsy findings in EPG5-related Vici syndrome with antenatal onset.Am J Med Genet A. 2017 Sep;173(9):2522-2527. doi: 10.1002/ajmg.a.38342. Epub 2017 Jul 27.
• [6] First description of a patient with Vici syndrome due to a mutation affecting the penultimate exon of EPG5 and review of the literature.Am J Med Genet A. 2014 Dec;164A(12):3170-5. doi: 10.1002/ajmg.a.36772. Epub 2014 Oct 20.
• [7] Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet. 2013 Jan;45(1):83-7. doi: 10.1038/ng.2497. Epub 2012 Dec 9.
• [8] C-myc/miR-150/EPG5 axis mediated dysfunction of autophagy promotes development of non-small cell lung cancer.Theranostics. 2019 Jul 9;9(18):5134-5148. doi: 10.7150/thno.34887. eCollection 2019.
• [9] Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis.Cell Host Microbe. 2016 Jan 13;19(1):102-13. doi: 10.1016/j.chom.2015.12.011.
• [10] EPG5 c.1007A>G mutation in a sibling pair with rapidly progressing Vici syndrome.Ann Hum Genet. 2020 Jan;84(1):80-86. doi: 10.1111/ahg.12337. Epub 2019 Jun 11.
• [11] EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.Brain. 2016 Mar;139(Pt 3):765-81. doi: 10.1093/brain/awv393.
• [12] Prenatal and postnatal presentations of corpus callosum agenesis with polymicrogyria caused by EGP5 mutation.Am J Med Genet A. 2017 Mar;173(3):706-711. doi: 10.1002/ajmg.a.38061. Epub 2017 Feb 7.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [21] 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.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.