Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT81Y80S)

• DOT Name: Cadherin-6 (CDH6)
• Synonyms: Kidney cadherin; K-cadherin
• Gene Name: CDH6
• UniProt ID: CADH6_HUMAN
• PDB ID: 5VEB
• Pfam ID: PF01049 ; PF00028
• Sequence:
  MRTYRYFLLLFWVGQPYPTLSTPLSKRTSGFPAKKRALELSGNSKNELNRSKRSWMWNQF
  FLLEEYTGSDYQYVGKLHSDQDRGDGSLKYILSGDGAGDLFIINENTGDIQATKRLDREE
  KPVYILRAQAINRRTGRPVEPESEFIIKIHDINDNEPIFTKEVYTATVPEMSDVGTFVVQ
  VTATDADDPTYGNSAKVVYSILQGQPYFSVESETGIIKTALLNMDRENREQYQVVIQAKD
  MGGQMGGLSGTTTVNITLTDVNDNPPRFPQSTYQFKTPESSPPGTPIGRIKASDADVGEN
  AEIEYSITDGEGLDMFDVITDQETQEGIITVKKLLDFEKKKVYTLKVEASNPYVEPRFLY
  LGPFKDSATVRIVVEDVDEPPVFSKLAYILQIREDAQINTTIGSVTAQDPDAARNPVKYS
  VDRHTDMDRIFNIDSGNGSIFTSKLLDRETLLWHNITVIATEINNPKQSSRVPLYIKVLD
  VNDNAPEFAEFYETFVCEKAKADQLIQTLHAVDKDDPYSGHQFSFSLAPEAASGSNFTIQ
  DNKDNTAGILTRKNGYNRHEMSTYLLPVVISDNDYPVQSSTGTVTVRVCACDHHGNMQSC
  HAEALIHPTGLSTGALVAILLCIVILLVTVVLFAALRRQRKKEPLIISKEDIRDNIVSYN
  DEGGGEEDTQAFDIGTLRNPEAIEDNKLRRDIVPEALFLPRRTPTARDNTDVRDFINQRL
  KENDTDPTAPPYDSLATYAYEGTGSVADSLSSLESVTTDADQDYDYLSDWGPRFKKLADM
  YGGVDSDKDS
• 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.
• Tissue Specificity: Highly expressed in brain, cerebellum, and kidney. Lung, pancreas, and gastric mucosa show a weak expression. Also expressed in certain liver and kidney carcinomas.
• Reactome Pathway: Adherens junctions interactions (R-HSA-418990)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cadherin-6 (CDH6).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cadherin-6 (CDH6).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cadherin-6 (CDH6).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cadherin-6 (CDH6).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Cadherin-6 (CDH6).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cadherin-6 (CDH6).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cadherin-6 (CDH6).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cadherin-6 (CDH6).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Cadherin-6 (CDH6).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Cadherin-6 (CDH6).	[10]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Cadherin-6 (CDH6).	[11]
Thalidomide	DM70BU5	Approved	Thalidomide increases the expression of Cadherin-6 (CDH6).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Cadherin-6 (CDH6).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Cadherin-6 (CDH6).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cadherin-6 (CDH6).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cadherin-6 (CDH6).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cadherin-6 (CDH6).	[16]
27-hydroxycholesterol	DM2L6OZ	Investigative	27-hydroxycholesterol decreases the expression of Cadherin-6 (CDH6).	[17]

1 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 increases the methylation of Cadherin-6 (CDH6).	[13]

References

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• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [12] Early Transcriptomic Changes upon Thalidomide Exposure Influence the Later Neuronal Development in Human Embryonic Stem Cell-Derived Spheres. Int J Mol Sci. 2020 Aug 3;21(15):5564. doi: 10.3390/ijms21155564.
• [13] 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.
• [14] 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.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [17] 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.