Details of Drug Off-Target (DOT)

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

• DOT Name: Frizzled-10 (FZD10)
• Synonyms: Fz-10; hFz10; FzE7; CD antigen CD350
• Gene Name: FZD10
• UniProt ID: FZD10_HUMAN
• PDB ID: 7X8Q; 7X8T
• Pfam ID: PF01534 ; PF01392
• Sequence:
  MQRPGPRLWLVLQVMGSCAAISSMDMERPGDGKCQPIEIPMCKDIGYNMTRMPNLMGHEN
  QREAAIQLHEFAPLVEYGCHGHLRFFLCSLYAPMCTEQVSTPIPACRVMCEQARLKCSPI
  MEQFNFKWPDSLDCRKLPNKNDPNYLCMEAPNNGSDEPTRGSGLFPPLFRPQRPHSAQEH
  PLKDGGPGRGGCDNPGKFHHVEKSASCAPLCTPGVDVYWSREDKRFAVVWLAIWAVLCFF
  SSAFTVLTFLIDPARFRYPERPIIFLSMCYCVYSVGYLIRLFAGAESIACDRDSGQLYVI
  QEGLESTGCTLVFLVLYYFGMASSLWWVVLTLTWFLAAGKKWGHEAIEANSSYFHLAAWA
  IPAVKTILILVMRRVAGDELTGVCYVGSMDVNALTGFVLIPLACYLVIGTSFILSGFVAL
  FHIRRVMKTGGENTDKLEKLMVRIGLFSVLYTVPATCVIACYFYERLNMDYWKILAAQHK
  CKMNNQTKTLDCLMAASIPAVEIFMVKIFMLLVVGITSGMWIWTSKTLQSWQQVCSRRLK
  KKSRRKPASVITSGGIYKKAQHPQKTHHGKYEIPAQSPTCV
• Function: Receptor for Wnt proteins. Functions in the canonical Wnt/beta-catenin signaling pathway. The canonical Wnt/beta-catenin signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues (Probable).
• Tissue Specificity: Highest levels in the placenta and fetal kidney, followed by fetal lung and brain. In adult brain, abundantly expressed in the cerebellum, followed by cerebral cortex, medulla and spinal cord; very low levels in total brain, frontal lobe, temporal lobe and putamen. Weak expression detected in adult brain, heart, lung, skeletal muscle, pancreas, spleen and prostate.
• KEGG Pathway:
  mTOR sig.ling pathway (hsa04150)
  Wnt sig.ling pathway (hsa04310)
  Hippo sig.ling pathway (hsa04390)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Melanogenesis (hsa04916)
  Cushing syndrome (hsa04934)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Basal cell carcinoma (hsa05217)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
• Reactome Pathway: Class B/2 (Secretin family receptors) (R-HSA-373080)

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 decreases the expression of Frizzled-10 (FZD10).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Frizzled-10 (FZD10).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Frizzled-10 (FZD10).	[3]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Frizzled-10 (FZD10).	[4]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Frizzled-10 (FZD10).	[5]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Frizzled-10 (FZD10).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Frizzled-10 (FZD10).	[4]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Frizzled-10 (FZD10).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Frizzled-10 (FZD10).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Frizzled-10 (FZD10).	[11]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Frizzled-10 (FZD10).	[12]

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 increases the methylation of Frizzled-10 (FZD10).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Frizzled-10 (FZD10).	[9]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [2] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [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] 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.
• [5] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [6] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [7] 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.
• [8] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [10] 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.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Deguelin inhibits growth of breast cancer cells by modulating the expression of key members of the Wnt signaling pathway. Cancer Prev Res (Phila). 2009 Nov;2(11):942-50. doi: 10.1158/1940-6207.CAPR-08-0232. Epub 2009 Oct 27.