Details of Drug Off-Target (DOT)

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

• DOT Name: EH domain-containing protein 1 (EHD1)
• Synonyms: PAST homolog 1; hPAST1; Testilin
• Gene Name: EHD1
• Related Disease:
  Malaria
  Thyroid gland papillary carcinoma
  Advanced cancer
  Autism
  Bardet-Biedl syndrome 1
  Bone osteosarcoma
  Deafness
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Osteosarcoma
  Schizophrenia
  Melanoma
  Neoplasm
  Cardiomyopathy
  Non-insulin dependent diabetes
  Obesity
• UniProt ID: EHD1_HUMAN
• PDB ID: 2JQ6; 2KFF; 2KFG; 2KFH; 2KSP
• Pfam ID: PF18150 ; PF00350 ; PF12763 ; PF16880
• Sequence:
  MFSWVSKDARRKKEPELFQTVAEGLRQLYAQKLLPLEEHYRFHEFHSPALEDADFDNKPM
  VLLVGQYSTGKTTFIRHLIEQDFPGMRIGPEPTTDSFIAVMHGPTEGVVPGNALVVDPRR
  PFRKLNAFGNAFLNRFMCAQLPNPVLDSISIIDTPGILSGEKQRISRGYDFAAVLEWFAE
  RVDRIILLFDAHKLDISDEFSEVIKALKNHEDKIRVVLNKADQIETQQLMRVYGALMWSL
  GKIINTPEVVRVYIGSFWSHPLLIPDNRKLFEAEEQDLFKDIQSLPRNAALRKLNDLIKR
  ARLAKVHAYIISSLKKEMPNVFGKESKKKELVNNLGEIYQKIEREHQISPGDFPSLRKMQ
  ELLQTQDFSKFQALKPKLLDTVDDMLANDIARLMVMVRQEESLMPSQVVKGGAFDGTMNG
  PFGHGYGEGAGEGIDDVEWVVGKDKPTYDEIFYTLSPVNGKITGANAKKEMVKSKLPNTV
  LGKIWKLADVDKDGLLDDEEFALANHLIKVKLEGHELPADLPPHLVPPSKRRHE
• Function: ATP- and membrane-binding protein that controls membrane reorganization/tubulation upon ATP hydrolysis. In vitro causes vesiculation of endocytic membranes. Acts in early endocytic membrane fusion and membrane trafficking of recycling endosomes. Recruited to endosomal membranes upon nerve growth factor stimulation, indirectly regulates neurite outgrowth. Plays a role in myoblast fusion. Involved in the unidirectional retrograde dendritic transport of endocytosed BACE1 and in efficient sorting of BACE1 to axons implicating a function in neuronal APP processing. Plays a role in the formation of the ciliary vesicle (CV), an early step in cilium biogenesis. Proposed to be required for the fusion of distal appendage vesicles (DAVs) to form the CV by recruiting SNARE complex component SNAP29. Is required for recruitment of transition zone proteins CEP290, RPGRIP1L, TMEM67 and B9D2, and of IFT20 following DAV reorganization before Rab8-dependent ciliary membrane extension. Required for the loss of CCP110 form the mother centriole essential for the maturation of the basal body during ciliogenesis.
• Tissue Specificity: Highly expressed in testis.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway: Factors involved in megakaryocyte development and platelet production (R-HSA-983231)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malaria	DISQ9Y50	Definitive	Genetic Variation	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Autism	DISV4V1Z	Strong	Genetic Variation	[4]
Bardet-Biedl syndrome 1	DISRLPZE	Strong	Biomarker	[5]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[6]
Deafness	DISKCLH4	Strong	Biomarker	[7]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Altered Expression	[3]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[6]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[10]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[11]
Neoplasm	DISZKGEW	moderate	Biomarker	[12]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[13]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[14]
Obesity	DIS47Y1K	Limited	Biomarker	[15]

2 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 EH domain-containing protein 1 (EHD1).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of EH domain-containing protein 1 (EHD1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of EH domain-containing protein 1 (EHD1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of EH domain-containing protein 1 (EHD1).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of EH domain-containing protein 1 (EHD1).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of EH domain-containing protein 1 (EHD1).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of EH domain-containing protein 1 (EHD1).	[22]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of EH domain-containing protein 1 (EHD1).	[23]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of EH domain-containing protein 1 (EHD1).	[24]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of EH domain-containing protein 1 (EHD1).	[25]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of EH domain-containing protein 1 (EHD1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of EH domain-containing protein 1 (EHD1).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of EH domain-containing protein 1 (EHD1).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of EH domain-containing protein 1 (EHD1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of EH domain-containing protein 1 (EHD1).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of EH domain-containing protein 1 (EHD1).	[31]

References

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• [2] Eps15 homology domain 1 promotes the evolution of papillary thyroid cancer by regulating endocytotic recycling of epidermal growth factor receptor.Oncol Lett. 2018 Oct;16(4):4263-4270. doi: 10.3892/ol.2018.9200. Epub 2018 Jul 24.
• [3] NF-B-driven improvement of EHD1 contributes to erlotinib resistance in EGFR-mutant lung cancers.Cell Death Dis. 2018 Apr 1;9(4):418. doi: 10.1038/s41419-018-0447-7.
• [4] Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder.Transl Psychiatry. 2013 May 28;3(5):e262. doi: 10.1038/tp.2013.38.
• [5] Evaluation and molecular characterization of EHD1, a candidate gene for Bardet-Biedl syndrome 1 (BBS1).Gene. 1999 Nov 15;240(1):227-32. doi: 10.1016/s0378-1119(99)00395-9.
• [6] The expression of Eps15 homology domain 1 is negatively correlated with disease-free survival and overall survival of osteosarcoma patients.J Orthop Surg Res. 2019 Apr 11;14(1):103. doi: 10.1186/s13018-019-1137-6.
• [7] EHD4 and CDH23 are interacting partners in cochlear hair cells.J Biol Chem. 2009 Jul 24;284(30):20121-9. doi: 10.1074/jbc.M109.025668. Epub 2009 Jun 1.
• [8] Characteristics of Japanese inflammatory bowel disease susceptibility loci.J Gastroenterol. 2014 Aug;49(8):1217-30. doi: 10.1007/s00535-013-0866-2. Epub 2013 Aug 13.
• [9] Targeting the IL-1/EHD1/TUBB3 axis overcomes resistance to EGFR-TKI in NSCLC.Oncogene. 2020 Feb;39(8):1739-1755. doi: 10.1038/s41388-019-1099-5. Epub 2019 Nov 18.
• [10] Dopaminergic mechanisms in the pathogenesis of schizophrenia.FASEB J. 1992 Apr;6(7):2413-21.
• [11] Metastatic melanoma of unknown primary resembles the genotype of cutaneous melanomas.Ann Oncol. 2014 Jan;25(1):246-50. doi: 10.1093/annonc/mdt411. Epub 2013 Nov 24.
• [12] Mammalian Eps15 homology domain 1 potentiates angiogenesis of non-small cell lung cancer by regulating 2AR signaling.J Exp Clin Cancer Res. 2019 Apr 25;38(1):174. doi: 10.1186/s13046-019-1162-7.
• [13] Targeted sequence capture and GS-FLX Titanium sequencing of 23 hypertrophic and dilated cardiomyopathy genes: implementation into diagnostics.J Med Genet. 2013 Sep;50(9):614-26. doi: 10.1136/jmedgenet-2012-101231. Epub 2013 Jun 19.
• [14] The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes.Pediatrics. 2001 Apr;107(4):E55. doi: 10.1542/peds.107.4.e55.
• [15] Differential expression of adipose tissue proteins between obesity-susceptible and -resistant rats fed a high-fat diet.Proteomics. 2011 Apr;11(8):1429-48. doi: 10.1002/pmic.201000515. Epub 2011 Feb 25.
• [16] 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.
• [17] 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.
• [18] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [19] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [20] 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.
• [21] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [22] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [23] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [24] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [25] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [30] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [31] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.