Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVX0E1Q)

• DOT Name: Cadherin-5 (CDH5)
• Synonyms: 7B4 antigen; Vascular endothelial cadherin; VE-cadherin; CD antigen CD144
• Gene Name: CDH5
• UniProt ID: CADH5_HUMAN
• Pfam ID: PF01049 ; PF00028
• Sequence:
  MQRLMMLLATSGACLGLLAVAAVAAAGANPAQRDTHSLLPTHRRQKRDWIWNQMHIDEEK
  NTSLPHHVGKIKSSVSRKNAKYLLKGEYVGKVFRVDAETGDVFAIERLDRENISEYHLTA
  VIVDKDTGENLETPSSFTIKVHDVNDNWPVFTHRLFNASVPESSAVGTSVISVTAVDADD
  PTVGDHASVMYQILKGKEYFAIDNSGRIITITKSLDREKQARYEIVVEARDAQGLRGDSG
  TATVLVTLQDINDNFPFFTQTKYTFVVPEDTRVGTSVGSLFVEDPDEPQNRMTKYSILRG
  DYQDAFTIETNPAHNEGIIKPMKPLDYEYIQQYSFIVEATDPTIDLRYMSPPAGNRAQVI
  INITDVDEPPIFQQPFYHFQLKENQKKPLIGTVLAMDPDAARHSIGYSIRRTSDKGQFFR
  VTKKGDIYNEKELDREVYPWYNLTVEAKELDSTGTPTGKESIVQVHIEVLDENDNAPEFA
  KPYQPKVCENAVHGQLVLQISAIDKDITPRNVKFKFILNTENNFTLTDNHDNTANITVKY
  GQFDREHTKVHFLPVVISDNGMPSRTGTSTLTVAVCKCNEQGEFTFCEDMAAQVGVSIQA
  VVAILLCILTITVITLLIFLRRRLRKQARAHGKSVPEIHEQLVTYDEEGGGEMDTTSYDV
  SVLNSVRRGGAKPPRPALDARPSLYAQVQKPPRHAPGAHGGPGEMAAMIEVKKDEADHDG
  DGPPYDTLHIYGYEGSESIAESLSSLGTDSSDSDVDYDFLNDWGPRFKMLAELYGSDPRE
  ELLY
• Function: Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. This cadherin may play a important role in endothelial cell biology through control of the cohesion and organization of the intercellular junctions. It associates with alpha-catenin forming a link to the cytoskeleton. Acts in concert with KRIT1 and PALS1 to establish and maintain correct endothelial cell polarity and vascular lumen. These effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for activation of PRKCZ and for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction.
• Tissue Specificity: Endothelial tissues and brain.
• KEGG Pathway:
  Cell adhesion molecules (hsa04514)
  Adherens junction (hsa04520)
  Leukocyte transendothelial migration (hsa04670)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  Adherens junctions interactions (R-HSA-418990)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cadherin-5 (CDH5).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cadherin-5 (CDH5).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cadherin-5 (CDH5).	[3]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cadherin-5 (CDH5).	[5]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Cadherin-5 (CDH5).	[6]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Cadherin-5 (CDH5).	[8]
Procaine	DM4LSNE	Approved	Procaine decreases the expression of Cadherin-5 (CDH5).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Cadherin-5 (CDH5).	[13]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Cadherin-5 (CDH5).	[14]
27-hydroxycholesterol	DM2L6OZ	Investigative	27-hydroxycholesterol decreases the expression of Cadherin-5 (CDH5).	[15]
Amarylline	DML9W2V	Investigative	Amarylline decreases the expression of Cadherin-5 (CDH5).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the phosphorylation of Cadherin-5 (CDH5).	[4]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the phosphorylation of Cadherin-5 (CDH5).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cadherin-5 (CDH5).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	Ethanol increases the uptake of Cadherin-5 (CDH5).	[7]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the localization of Cadherin-5 (CDH5).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the localization of Cadherin-5 (CDH5).	[11]

References

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• [2] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [3] 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.
• [4] Disruption of endothelial adherens junction by invasive breast cancer cells is mediated by reactive oxygen species and is attenuated by AHCC. Life Sci. 2013 Dec 18;93(25-26):994-1003. doi: 10.1016/j.lfs.2013.10.027. Epub 2013 Nov 6.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther. 2008 Oct;7(10):1607-18.
• [7] Ethanol disrupts vascular endothelial barrier: implication in cancer metastasis. Toxicol Sci. 2012 May;127(1):42-53. doi: 10.1093/toxsci/kfs087. Epub 2012 Feb 13.
• [8] Chlorpyrifos, permethrin and cyfluthrin effect on cell survival, permeability, and tight junction in an in-vitro model of the human blood-brain barrier (BBB). Neurotoxicology. 2022 Dec;93:152-162. doi: 10.1016/j.neuro.2022.09.010. Epub 2022 Sep 24.
• [9] Hydrocortisone enhances the barrier properties of HBMEC/ci, a brain microvascular endothelial cell line, through mesenchymal-to-endothelial transition-like effects. Fluids Barriers CNS. 2015 Mar 5;12:7. doi: 10.1186/s12987-015-0003-0. eCollection 2015.
• [10] H(1)R mediates local anesthetic-induced vascular permeability in angioedema. Toxicol Appl Pharmacol. 2020 Apr 1;392:114921. doi: 10.1016/j.taap.2020.114921. Epub 2020 Feb 12.
• [11] Inhibition of vascular endothelial growth factor-induced angiogenesis by resveratrol through interruption of Src-dependent vascular endothelial cadherin tyrosine phosphorylation. Mol Pharmacol. 2003 Nov;64(5):1029-36. doi: 10.1124/mol.64.5.1029.
• [12] 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.
• [13] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [14] Non-nutritional sweeteners effects on endothelial vascular function. Toxicol In Vitro. 2020 Feb;62:104694. doi: 10.1016/j.tiv.2019.104694. Epub 2019 Oct 23.
• [15] The 14-3-3/GSK-3/-catenin complex regulates EndMT induced by 27-hydroxycholesterol in HUVECs and promotes the migration of breast cancer cells. Cell Biol Toxicol. 2021 Aug;37(4):515-529. doi: 10.1007/s10565-020-09564-y. Epub 2020 Nov 1.
• [16] Lycorine hydrochloride selectively inhibits human ovarian cancer cell proliferation and tumor neovascularization with very low toxicity. Toxicol Lett. 2013 Apr 12;218(2):174-85. doi: 10.1016/j.toxlet.2013.01.018. Epub 2013 Jan 31.