Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTX391J)

• DOT Name: EH domain-containing protein 2 (EHD2)
• Synonyms: PAST homolog 2
• Gene Name: EHD2
• Related Disease:
  Arthritis
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Clear cell renal carcinoma
  Congestive heart failure
  Deafness
  Esophageal squamous cell carcinoma
  Neoplasm
  Neuralgia
  Thyroid gland papillary carcinoma
• UniProt ID: EHD2_HUMAN
• Pfam ID: PF18150 ; PF00350 ; PF12763 ; PF16880
• Sequence:
  MFSWLKRGGARGQQPEAIRTVTSALKELYRTKLLPLEEHYRFGAFHSPALEDADFDGKPM
  VLVAGQYSTGKTSFIQYLLEQEVPGSRVGPEPTTDCFVAVMHGDTEGTVPGNALVVDPDK
  PFRKLNPFGNTFLNRFMCAQLPNQVLESISIIDTPGILSGAKQRVSRGYDFPAVLRWFAE
  RVDLIILLFDAHKLEISDEFSEAIGALRGHEDKIRVVLNKADMVETQQLMRVYGALMWAL
  GKVVGTPEVLRVYIGSFWSQPLLVPDNRRLFELEEQDLFRDIQGLPRHAALRKLNDLVKR
  ARLVRVHAYIISYLKKEMPSVFGKENKKKQLILKLPVIFAKIQLEHHISPGDFPDCQKMQ
  ELLMAHDFTKFHSLKPKLLEALDEMLTHDIAKLMPLLRQEELESTEVGVQGGAFEGTHMG
  PFVERGPDEAMEDGEEGSDDEAEWVVTKDKSKYDEIFYNLAPADGKLSGSKAKTWMVGTK
  LPNSVLGRIWKLSDVDRDGMLDDEEFALASHLIEAKLEGHGLPANLPRRLVPPSKRRHKG
  SAE
• Function: ATP- and membrane-binding protein that controls membrane reorganization/tubulation upon ATP hydrolysis. Plays a role in membrane trafficking between the plasma membrane and endosomes. Important for the internalization of GLUT4. Required for fusion of myoblasts to skeletal muscle myotubes. Required for normal translocation of FER1L5 to the plasma membrane. Regulates the equilibrium between cell surface-associated and cell surface-dissociated caveolae by constraining caveolae at the cell membrane.
• Tissue Specificity: Highly expressed in heart and moderately expressed in placenta, lung, and skeletal muscle.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway: Factors involved in megakaryocyte development and platelet production (R-HSA-983231)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Deafness	DISKCLH4	Strong	Altered Expression	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Neuralgia	DISWO58J	Strong	Biomarker	[7]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	EH domain-containing protein 2 (EHD2) affects the response to substance of Fluorouracil.	[21]

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 EH domain-containing protein 2 (EHD2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of EH domain-containing protein 2 (EHD2).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of EH domain-containing protein 2 (EHD2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of EH domain-containing protein 2 (EHD2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of EH domain-containing protein 2 (EHD2).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of EH domain-containing protein 2 (EHD2).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of EH domain-containing protein 2 (EHD2).	[13]
Marinol	DM70IK5	Approved	Marinol increases the expression of EH domain-containing protein 2 (EHD2).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of EH domain-containing protein 2 (EHD2).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of EH domain-containing protein 2 (EHD2).	[16]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of EH domain-containing protein 2 (EHD2).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of EH domain-containing protein 2 (EHD2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of EH domain-containing protein 2 (EHD2).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of EH domain-containing protein 2 (EHD2).	[17]

References

• [1] Selective Activation of Tumor Necrosis Factor Receptor II Induces Antiinflammatory Responses and Alleviates Experimental Arthritis.Arthritis Rheumatol. 2018 May;70(5):722-735. doi: 10.1002/art.40413. Epub 2018 Mar 11.
• [2] Effect of EH domain containing protein 2 on the biological behavior of clear cell renal cell carcinoma.Hum Exp Toxicol. 2019 Aug;38(8):927-937. doi: 10.1177/0960327119842241. Epub 2019 Apr 17.
• [3] Decreased expression and prognostic role of EHD2 in human breast carcinoma: correlation with E-cadherin.J Mol Histol. 2015 Apr;46(2):221-31. doi: 10.1007/s10735-015-9614-7. Epub 2015 Mar 12.
• [4] Cardiomyocyte damage control in heart failure and the role of the sarcolemma.J Muscle Res Cell Motil. 2019 Dec;40(3-4):319-333. doi: 10.1007/s10974-019-09539-5. Epub 2019 Sep 13.
• [5] 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.
• [6] Effects of EHD2 interference on migration of esophageal squamous cell carcinoma.Med Oncol. 2013 Mar;30(1):396. doi: 10.1007/s12032-012-0396-4. Epub 2013 Jan 25.
• [7] TNFR2 promotes Treg-mediated recovery from neuropathic pain across sexes.Proc Natl Acad Sci U S A. 2019 Aug 20;116(34):17045-17050. doi: 10.1073/pnas.1902091116. Epub 2019 Aug 7.
• [8] Prognostic implication of histological features associated with EHD2 expression in papillary thyroid carcinoma.PLoS One. 2017 Mar 30;12(3):e0174737. doi: 10.1371/journal.pone.0174737. eCollection 2017.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] 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.
• [14] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [15] 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.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] 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.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] 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.
• [20] 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.
• [21] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.