Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTK3F6E)

• DOT Name: Frizzled-7 (FZD7)
• Synonyms: Fz-7; hFz7; FzE3
• Gene Name: FZD7
• UniProt ID: FZD7_HUMAN
• PDB ID: 4Z33; 5T44; 5URV; 5WBS; 6NE2; 6NE4; 6O3A; 6O3B; 7EVW
• Pfam ID: PF01534 ; PF01392
• Sequence:
  MRDPGAAAPLSSLGLCALVLALLGALSAGAGAQPYHGEKGISVPDHGFCQPISIPLCTDI
  AYNQTILPNLLGHTNQEDAGLEVHQFYPLVKVQCSPELRFFLCSMYAPVCTVLDQAIPPC
  RSLCERARQGCEALMNKFGFQWPERLRCENFPVHGAGEICVGQNTSDGSGGPGGGPTAYP
  TAPYLPDLPFTALPPGASDGRGRPAFPFSCPRQLKVPPYLGYRFLGERDCGAPCEPGRAN
  GLMYFKEEERRFARLWVGVWSVLCCASTLFTVLTYLVDMRRFSYPERPIIFLSGCYFMVA
  VAHVAGFLLEDRAVCVERFSDDGYRTVAQGTKKEGCTILFMVLYFFGMASSIWWVILSLT
  WFLAAGMKWGHEAIEANSQYFHLAAWAVPAVKTITILAMGQVDGDLLSGVCYVGLSSVDA
  LRGFVLAPLFVYLFIGTSFLLAGFVSLFRIRTIMKHDGTKTEKLEKLMVRIGVFSVLYTV
  PATIVLACYFYEQAFREHWERTWLLQTCKSYAVPCPPGHFPPMSPDFTVFMIKYLMTMIV
  GITTGFWIWSGKTLQSWRRFYHRLSHSSKGETAV
• Function: Receptor for Wnt proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which 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. Activation by WNT8 induces expression of beta-catenin target genes. Following ligand activation, binds to CCDC88C/DAPLE which displaces DVL1 from FZD7 and leads to inhibition of canonical Wnt signaling, activation of G-proteins by CCDC88C and triggering of non-canonical Wnt responses. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues; (Microbial infection) Acts as a receptor for C.difficile toxin TcdB in the colonic epithelium.
• Tissue Specificity: High expression in adult skeletal muscle and fetal kidney, followed by fetal lung, adult heart, brain, and placenta. Specifically expressed in squamous cell esophageal carcinomas.
• 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:
  PCP/CE pathway (R-HSA-4086400)
  Asymmetric localization of PCP proteins (R-HSA-4608870)
  WNT5 (R-HSA-9673324)
  Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Artesunate	DMR27C8	Approved	Frizzled-7 (FZD7) increases the response to substance of Artesunate.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Frizzled-7 (FZD7).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Frizzled-7 (FZD7).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Frizzled-7 (FZD7).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Frizzled-7 (FZD7).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Frizzled-7 (FZD7).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Frizzled-7 (FZD7).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Frizzled-7 (FZD7).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Frizzled-7 (FZD7).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Frizzled-7 (FZD7).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Frizzled-7 (FZD7).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Frizzled-7 (FZD7).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Frizzled-7 (FZD7).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Frizzled-7 (FZD7).	[12]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Frizzled-7 (FZD7).	[9]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Frizzled-7 (FZD7).	[13]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Frizzled-7 (FZD7).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Frizzled-7 (FZD7).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Frizzled-7 (FZD7).	[12]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Frizzled-7 (FZD7).	[12]
APR-246	DMNFADH	Phase 2	APR-246 increases the expression of Frizzled-7 (FZD7).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Frizzled-7 (FZD7).	[1]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Frizzled-7 (FZD7).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Frizzled-7 (FZD7).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Frizzled-7 (FZD7).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Frizzled-7 (FZD7).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Frizzled-7 (FZD7).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Frizzled-7 (FZD7).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Frizzled-7 (FZD7).	[23]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Frizzled-7 (FZD7).	[24]

References

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• [23] 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.
• [24] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [25] Factors determining sensitivity or resistance of tumor cell lines towards artesunate. Chem Biol Interact. 2010 Apr 15;185(1):42-52.