Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGLZIE0)

• DOT Name: Frizzled-4 (FZD4)
• Synonyms: Fz-4; hFz4; FzE4; CD antigen CD344
• Gene Name: FZD4
• Related Disease:
  Disorder of orbital region
  Exudative vitreoretinopathy
  Exudative vitreoretinopathy 1
  Uveal Melanoma
  Vitreoretinal degeneration
  Acute myelogenous leukaemia
  Analgesia
  Bipolar disorder
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Cardiovascular disease
  Colorectal carcinoma
  Congestive heart failure
  Cystic fibrosis
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  Hereditary hemochromatosis
  Isolated cleft palate
  Kaposi sarcoma
  Metabolic disorder
  Multiple sclerosis
  Nephrogenic diabetes insipidus
  Non-insulin dependent diabetes
  Norrie disease
  Obesity
  Pancreatic neuroendocrine tumor
  Retinopathy
  Rhegmatogenous retinal detachment
  Schizophrenia
  Syndactyly
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Advanced cancer
  Autoimmune disease
  High blood pressure
  Persistent hyperplastic primary vitreous
  Prostate cancer
  Prostate carcinoma
  Skin cancer
  Alzheimer disease
  Asthma
  Inflammatory bowel disease
  Non-small-cell lung cancer
  Osteoporosis
• UniProt ID: FZD4_HUMAN
• PDB ID: 5BPB; 5BPQ; 5BQC; 5BQE; 5CL1; 5CM4; 5UWG; 6BD4; 6NE1
• Pfam ID: PF01534 ; PF01392
• Sequence:
  MAWRGAGPSVPGAPGGVGLSLGLLLQLLLLLGPARGFGDEEERRCDPIRISMCQNLGYNV
  TKMPNLVGHELQTDAELQLTTFTPLIQYGCSSQLQFFLCSVYVPMCTEKINIPIGPCGGM
  CLSVKRRCEPVLKEFGFAWPESLNCSKFPPQNDHNHMCMEGPGDEEVPLPHKTPIQPGEE
  CHSVGTNSDQYIWVKRSLNCVLKCGYDAGLYSRSAKEFTDIWMAVWASLCFISTAFTVLT
  FLIDSSRFSYPERPIIFLSMCYNIYSIAYIVRLTVGRERISCDFEEAAEPVLIQEGLKNT
  GCAIIFLLMYFFGMASSIWWVILTLTWFLAAGLKWGHEAIEMHSSYFHIAAWAIPAVKTI
  VILIMRLVDADELTGLCYVGNQNLDALTGFVVAPLFTYLVIGTLFIAAGLVALFKIRSNL
  QKDGTKTDKLERLMVKIGVFSVLYTVPATCVIACYFYEISNWALFRYSADDSNMAVEMLK
  IFMSLLVGITSGMWIWSAKTLHTWQKCSNRLVNSGKVKREKRGNGWVKPGKGSETVV
• Function: Receptor for Wnt proteins. Most frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes. Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP). In retina, it can be activated by Wnt protein-binding and also by Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs. 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.
• Tissue Specificity: Almost ubiquitous . Largely expressed in adult heart, skeletal muscle, ovary, and fetal kidney . Moderate amounts in adult liver, kidney, pancreas, spleen, and fetal lung, and small amounts in placenta, adult lung, prostate, testis, colon, fetal brain and 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:
  Ca2+ pathway (R-HSA-4086398)
  Asymmetric localization of PCP proteins (R-HSA-4608870)
  Regulation of FZD by ubiquitination (R-HSA-4641263)
  WNT5A-dependent internalization of FZD4 (R-HSA-5099900)
  Signaling by RNF43 mutants (R-HSA-5340588)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Disorder of orbital region	DISH0ECJ	Definitive	Biomarker	[1]
Exudative vitreoretinopathy	DISWN0TG	Definitive	Autosomal dominant	[2]
Exudative vitreoretinopathy 1	DISRC9YA	Definitive	Autosomal dominant	[3]
Uveal Melanoma	DISA7ZGL	Definitive	Genetic Variation	[4]
Vitreoretinal degeneration	DISVPRKD	Definitive	Genetic Variation	[5]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[6]
Analgesia	DISK3TVI	Strong	Biomarker	[7]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[8]
Bladder cancer	DISUHNM0	Strong	Biomarker	[9]
Breast cancer	DIS7DPX1	Strong	Biomarker	[10]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[10]
Cardiac failure	DISDC067	Strong	Biomarker	[11]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[12]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[11]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[13]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[15]
Hereditary hemochromatosis	DISVG5MT	Strong	Biomarker	[16]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[17]
Kaposi sarcoma	DISC1H1Z	Strong	Biomarker	[18]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[19]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[20]
Nephrogenic diabetes insipidus	DISKNSJK	Strong	Biomarker	[21]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[22]
Norrie disease	DISOCDDU	Strong	Biomarker	[23]
Obesity	DIS47Y1K	Strong	Biomarker	[24]
Pancreatic neuroendocrine tumor	DISDMPU0	Strong	Biomarker	[25]
Retinopathy	DISB4B0F	Strong	Biomarker	[23]
Rhegmatogenous retinal detachment	DISLE27J	Strong	Biomarker	[26]
Schizophrenia	DISSRV2N	Strong	Biomarker	[27]
Syndactyly	DISZK2BT	Strong	Biomarker	[17]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[28]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[9]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[9]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[29]
Autoimmune disease	DISORMTM	moderate	Biomarker	[30]
High blood pressure	DISY2OHH	moderate	Biomarker	[31]
Persistent hyperplastic primary vitreous	DISABPH6	Supportive	Autosomal dominant	[32]
Prostate cancer	DISF190Y	Disputed	Biomarker	[33]
Prostate carcinoma	DISMJPLE	Disputed	Biomarker	[33]
Skin cancer	DISTM18U	Disputed	Altered Expression	[34]
Alzheimer disease	DISF8S70	Limited	Biomarker	[35]
Asthma	DISW9QNS	Limited	Biomarker	[36]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[37]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[38]
Osteoporosis	DISF2JE0	Limited	Biomarker	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Frizzled-4 (FZD4).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Frizzled-4 (FZD4).	[41]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Frizzled-4 (FZD4).	[42]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Frizzled-4 (FZD4).	[43]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Frizzled-4 (FZD4).	[44]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Frizzled-4 (FZD4).	[45]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Frizzled-4 (FZD4).	[46]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Frizzled-4 (FZD4).	[47]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Frizzled-4 (FZD4).	[48]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Frizzled-4 (FZD4).	[46]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Frizzled-4 (FZD4).	[49]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Frizzled-4 (FZD4).	[47]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Frizzled-4 (FZD4).	[50]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Frizzled-4 (FZD4).	[51]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Frizzled-4 (FZD4).	[41]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Frizzled-4 (FZD4).	[52]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Frizzled-4 (FZD4).	[53]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Frizzled-4 (FZD4).	[54]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Frizzled-4 (FZD4).	[55]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Frizzled-4 (FZD4).	[56]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Frizzled-4 (FZD4).	[57]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Frizzled-4 (FZD4).	[58]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Frizzled-4 (FZD4).	[59]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Frizzled-4 (FZD4).	[60]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Frizzled-4 (FZD4).	[61]

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