Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT952ML1)

• DOT Name: Frizzled-2 (FZD2)
• Synonyms: Fz-2; hFz2; FzE2
• Gene Name: FZD2
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Autosomal dominant omodysplasia
  Carcinoma of esophagus
  Colon cancer
  Colonic neoplasm
  Congenital diaphragmatic hernia
  Esophageal cancer
  Familial adenomatous polyposis
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Leiomyoma
  Medulloblastoma
  Myelofibrosis
  Neoplasm
  Neoplasm of esophagus
  Primary myelofibrosis
  Prostate cancer
  Prostate carcinoma
  Psoriasis
  Robinow syndrome
  Stomach cancer
  Uterine fibroids
  Cervical carcinoma
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Autosomal dominant Robinow syndrome
  Amyotrophic lateral sclerosis
  Myocardial infarction
  Omodysplasia
  Osteochondrodysplasia
  Skeletal dysplasia
• UniProt ID: FZD2_HUMAN
• PDB ID: 6C0B; 7N95; 7N97; 7N9S; 7X8P
• Pfam ID: PF01534 ; PF01392
• Sequence:
  MRPRSALPRLLLPLLLLPAAGPAQFHGEKGISIPDHGFCQPISIPLCTDIAYNQTIMPNL
  LGHTNQEDAGLEVHQFYPLVKVQCSPELRFFLCSMYAPVCTVLEQAIPPCRSICERARQG
  CEALMNKFGFQWPERLRCEHFPRHGAEQICVGQNHSEDGAPALLTTAPPPGLQPGAGGTP
  GGPGGGGAPPRYATLEHPFHCPRVLKVPSYLSYKFLGERDCAAPCEPARPDGSMFFSQEE
  TRFARLWILTWSVLCCASTFFTVTTYLVDMQRFRYPERPIIFLSGCYTMVSVAYIAGFVL
  QERVVCNERFSEDGYRTVVQGTKKEGCTILFMMLYFFSMASSIWWVILSLTWFLAAGMKW
  GHEAIEANSQYFHLAAWAVPAVKTITILAMGQIDGDLLSGVCFVGLNSLDPLRGFVLAPL
  FVYLFIGTSFLLAGFVSLFRIRTIMKHDGTKTEKLERLMVRIGVFSVLYTVPATIVIACY
  FYEQAFREHWERSWVSQHCKSLAIPCPAHYTPRMSPDFTVYMIKYLMTLIVGITSGFWIW
  SGKTLHSWRKFYTRLTNSRHGETTV
• Function: Receptor for Wnt proteins. Most of 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. 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. TcdB occupies the binding site for Wnt-adducted palmitoleate in frizzled receptors and TcdB-binding prevents Wnt-binding and downstream Wnt signaling.
• Tissue Specificity: Widely expressed. In the adult, mainly found in heart, placenta, skeletal muscle, lung, kidney, pancreas, prostate, testis, ovary and colon. In the fetus, expressed in brain, lung and kidney. Low levels in fetal liver.
• 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)
  Ca2+ pathway (R-HSA-4086398)
  Asymmetric localization of PCP proteins (R-HSA-4608870)
  Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262)
  WNT5A-dependent internalization of FZD2, FZD5 and ROR2 (R-HSA-5140745)
  TCF dependent signaling in response to WNT (R-HSA-201681)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Autosomal dominant omodysplasia	DISWJE4V	Strong	Autosomal dominant	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[5]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Genetic Variation	[6]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[4]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[9]
Leiomyoma	DISLDDFN	Strong	Altered Expression	[10]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[11]
Myelofibrosis	DISIMP21	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[4]
Primary myelofibrosis	DIS6L0CN	Strong	Altered Expression	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[13]
Psoriasis	DIS59VMN	Strong	Genetic Variation	[14]
Robinow syndrome	DISK1CNU	Strong	GermlineCausalMutation	[15]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Uterine fibroids	DISBZRMJ	Strong	Altered Expression	[10]
Cervical carcinoma	DIST4S00	moderate	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[2]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[17]
Autosomal dominant Robinow syndrome	DIS94N80	Supportive	Autosomal dominant	[15]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[18]
Myocardial infarction	DIS655KI	Limited	Biomarker	[19]
Omodysplasia	DISREAME	Limited	Genetic Variation	[20]
Osteochondrodysplasia	DIS9SPWW	Limited	Genetic Variation	[20]
Skeletal dysplasia	DIS5Z8U6	Limited	Genetic Variation	[20]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Frizzled-2 (FZD2) affects the response to substance of Fluorouracil.	[42]
Mitoxantrone	DMM39BF	Approved	Frizzled-2 (FZD2) affects the response to substance of Mitoxantrone.	[42]

23 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-2 (FZD2).	[21]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Frizzled-2 (FZD2).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Frizzled-2 (FZD2).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Frizzled-2 (FZD2).	[24]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Frizzled-2 (FZD2).	[25]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Frizzled-2 (FZD2).	[26]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Frizzled-2 (FZD2).	[27]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Frizzled-2 (FZD2).	[28]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Frizzled-2 (FZD2).	[29]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Frizzled-2 (FZD2).	[30]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Frizzled-2 (FZD2).	[31]
Marinol	DM70IK5	Approved	Marinol increases the expression of Frizzled-2 (FZD2).	[32]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Frizzled-2 (FZD2).	[29]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Frizzled-2 (FZD2).	[33]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Frizzled-2 (FZD2).	[34]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Frizzled-2 (FZD2).	[35]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Frizzled-2 (FZD2).	[36]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Frizzled-2 (FZD2).	[29]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Frizzled-2 (FZD2).	[37]
T83193	DMHO29Y	Patented	T83193 decreases the expression of Frizzled-2 (FZD2).	[38]
Calphostin C	DM9X2D0	Terminated	Calphostin C increases the expression of Frizzled-2 (FZD2).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Frizzled-2 (FZD2).	[41]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Frizzled-2 (FZD2).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Frizzled-2 (FZD2).	[40]

References

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