Details of Drug Off-Target (DOT)

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

DOT Name	Frizzled-1 (FZD1)
Synonyms	Fz-1; hFz1; FzE1
Gene Name	FZD1
Related Disease	Acute myelogenous leukaemia ( ) Adenoma ( ) Bone osteosarcoma ( ) Clear cell renal carcinoma ( ) Colon cancer ( ) Colon carcinoma ( ) Colonic neoplasm ( ) Depression ( ) Familial adenomatous polyposis ( ) Hepatocellular carcinoma ( ) Hypertrophic cardiomyopathy ( ) Lung cancer ( ) Lung carcinoma ( ) Matthew-Wood syndrome ( ) Medulloblastoma ( ) Myocardial infarction ( ) Non-small-cell lung cancer ( ) Osteoarthritis ( ) Osteosarcoma ( ) Ovarian neoplasm ( ) Papillary renal cell carcinoma ( ) Primary hyperparathyroidism ( ) Prostate cancer ( ) Prostate carcinoma ( ) Schizophrenia ( ) Ulcerative colitis ( ) Breast cancer ( ) Breast carcinoma ( ) Exudative vitreoretinopathy ( ) Metastatic malignant neoplasm ( ) Neuroblastoma ( ) Advanced cancer ( ) Brain infarction ( ) Childhood kidney Wilms tumor ( ) Colorectal carcinoma ( ) Invasive breast carcinoma ( ) Microphthalmia ( ) Neoplasm ( ) Thyroid gland follicular carcinoma ( ) Thyroid gland papillary carcinoma ( ) Thyroid tumor ( ) Triple negative breast cancer ( ) Wilms tumor ( )
UniProt ID	FZD1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF01534 ; PF01392
Sequence	MAEEEAPKKSRAAGGGASWELCAGALSARLAEEGSGDAGGRRRPPVDPRRLARQLLLLLW LLEAPLLLGVRAQAAGQGPGQGPGPGQQPPPPPQQQQSGQQYNGERGISVPDHGYCQPIS IPLCTDIAYNQTIMPNLLGHTNQEDAGLEVHQFYPLVKVQCSAELKFFLCSMYAPVCTVL EQALPPCRSLCERARQGCEALMNKFGFQWPDTLKCEKFPVHGAGELCVGQNTSDKGTPTP SLLPEFWTSNPQHGGGGHRGGFPGGAGASERGKFSCPRALKVPSYLNYHFLGEKDCGAPC EPTKVYGLMYFGPEELRFSRTWIGIWSVLCCASTLFTVLTYLVDMRRFSYPERPIIFLSG CYTAVAVAYIAGFLLEDRVVCNDKFAEDGARTVAQGTKKEGCTILFMMLYFFSMASSIWW VILSLTWFLAAGMKWGHEAIEANSQYFHLAAWAVPAIKTITILALGQVDGDVLSGVCFVG LNNVDALRGFVLAPLFVYLFIGTSFLLAGFVSLFRIRTIMKHDGTKTEKLEKLMVRIGVF SVLYTVPATIVIACYFYEQAFRDQWERSWVAQSCKSYAIPCPHLQAGGGAPPHPPMSPDF TVFMIKYLMTLIVGITSGFWIWSGKTLNSWRKFYTRLTNSKQGETTV
Function	Receptor for Wnt proteins. Activated by WNT3A, WNT3, WNT1 and to a lesser extent WNT2, but apparently not by WNT4, WNT5A, WNT5B, WNT6, WNT7A or WNT7B. Contradictory results showing activation by WNT7B have been described for mouse. 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); (Microbial infection) Acts as a receptor for C.difficile toxin TcdB in the colonic epithelium.
Tissue Specificity	Expressed in adult heart, placenta, lung, kidney, pancreas, prostate, and ovary and in fetal lung and kidney.
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 ) PCP/CE pathway (R-HSA-4086400 ) Asymmetric localization of PCP proteins (R-HSA-4608870 ) Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262 ) TCF dependent signaling in response to WNT (R-HSA-201681 )

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[6]
Depression	DIS3XJ69	Strong	Biomarker	[7]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Altered Expression	[10]
Lung cancer	DISCM4YA	Strong	Altered Expression	[11]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[11]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[12]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[13]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[14]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[11]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[15]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[3]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[16]
Papillary renal cell carcinoma	DIS25HBV	Strong	Altered Expression	[4]
Primary hyperparathyroidism	DISB4U1Q	Strong	Altered Expression	[17]
Prostate cancer	DISF190Y	Strong	Biomarker	[18]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[18]
Schizophrenia	DISSRV2N	Strong	Biomarker	[19]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[20]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[21]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[21]
Exudative vitreoretinopathy	DISWN0TG	moderate	Genetic Variation	[22]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[23]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[24]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[25]
Brain infarction	DISPPGYK	Limited	Altered Expression	[26]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Biomarker	[27]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[28]
Invasive breast carcinoma	DISANYTW	Limited	Altered Expression	[29]
Microphthalmia	DISGEBES	Limited	Biomarker	[30]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]
Thyroid gland follicular carcinoma	DISFK2QT	Limited	Altered Expression	[31]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[31]
Thyroid tumor	DISLVKMD	Limited	Altered Expression	[31]
Triple negative breast cancer	DISAMG6N	Limited	Genetic Variation	[32]
Wilms tumor	DISB6T16	Limited	Biomarker	[27]
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⏷ Show the Full List of 43 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas 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 increases the expression of Frizzled-1 (FZD1).	[33]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Frizzled-1 (FZD1).	[34]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Frizzled-1 (FZD1).	[35]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Frizzled-1 (FZD1).	[36]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Frizzled-1 (FZD1).	[37]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Frizzled-1 (FZD1).	[38]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Frizzled-1 (FZD1).	[39]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Frizzled-1 (FZD1).	[40]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Frizzled-1 (FZD1).	[41]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Frizzled-1 (FZD1).	[37]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Frizzled-1 (FZD1).	[37]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Frizzled-1 (FZD1).	[37]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Frizzled-1 (FZD1).	[37]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Frizzled-1 (FZD1).	[37]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Frizzled-1 (FZD1).	[43]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Frizzled-1 (FZD1).	[44]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Frizzled-1 (FZD1).	[47]
Calphostin C	DM9X2D0	Terminated	Calphostin C increases the expression of Frizzled-1 (FZD1).	[48]
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⏷ Show the Full List of 18 Drug(s)

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Niclosamide	DMJAGXQ	Approved	Niclosamide affects the localization of Frizzled-1 (FZD1).	[42]
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2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Camptothecin decreases the methylation of Frizzled-1 (FZD1).	[45]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Frizzled-1 (FZD1).	[46]
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References

1	Knockdown of the Wnt receptor Frizzled-1 (FZD1) reduces MDR1/P-glycoprotein expression in multidrug resistant leukemic cells and inhibits leukemic cell proliferation.Leuk Res. 2018 Apr;67:99-108. doi: 10.1016/j.leukres.2018.01.020. Epub 2018 Jan 31.
2	Frizzled-7 Is Required for Wnt Signaling in Gastric Tumors with and Without Apc Mutations.Cancer Res. 2019 Mar 1;79(5):970-981. doi: 10.1158/0008-5472.CAN-18-2095. Epub 2019 Jan 8.
3	Sox9 regulates hyperexpression of Wnt1 and Fzd1 in human osteosarcoma tissues and cells.Int J Clin Exp Pathol. 2014 Jul 15;7(8):4795-805. eCollection 2014.
4	Overexpression of FZD1 is Associated with a Good Prognosis and Resistance of Sunitinib in Clear Cell Renal Cell Carcinoma.J Cancer. 2019 Jan 29;10(5):1237-1251. doi: 10.7150/jca.28662. eCollection 2019.
5	Post-translational glycoprotein modifications regulate colon cancer stem cells and colon adenoma progression in Apc(min/+) mice through altered Wnt receptor signaling.J Biol Chem. 2014 Nov 7;289(45):31534-49. doi: 10.1074/jbc.M114.602680. Epub 2014 Oct 1.
6	DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer.Cancer Res. 2017 Dec 1;77(23):6562-6575. doi: 10.1158/0008-5472.CAN-17-1570. Epub 2017 Oct 11.
7	Analysis of target genes regulated by chronic electroconvulsive therapy reveals role for Fzd6 in depression.Biol Psychiatry. 2012 Jan 1;71(1):51-8. doi: 10.1016/j.biopsych.2011.08.004. Epub 2011 Sep 19.
8	APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway.Dev Cell. 2018 Mar 12;44(5):566-581.e8. doi: 10.1016/j.devcel.2018.02.013.
9	Dynamic expression of ZNF382 and its tumor-suppressor role in hepatitis B virus-related hepatocellular carcinogenesis.Oncogene. 2019 Jun;38(24):4804-4819. doi: 10.1038/s41388-019-0759-9. Epub 2019 Feb 25.
10	Identification of the difference in the pathogenesis in heart failure arising from different etiologies using a microarray dataset.Clinics (Sao Paulo). 2017 Oct;72(10):600-608. doi: 10.6061/clinics/2017(10)03.
11	miR-135b reverses chemoresistance of non-small cell lung cancer cells by downregulation of FZD1.Biomed Pharmacother. 2016 Dec;84:123-129. doi: 10.1016/j.biopha.2016.09.027. Epub 2016 Sep 16.
12	Overexpression of FZD1 and CAIX are Associated with Invasion, Metastasis, and Poor-Prognosis of the Pancreatic Ductal Adenocarcinoma.Pathol Oncol Res. 2018 Oct;24(4):899-906. doi: 10.1007/s12253-017-0284-5. Epub 2017 Sep 18.
13	Expression profile of frizzled receptors in human medulloblastomas.J Neurooncol. 2012 Jan;106(2):271-80. doi: 10.1007/s11060-011-0682-6. Epub 2011 Aug 18.
14	Recombinant frizzled1 protein attenuated cardiac hypertrophy after myocardial infarction via the canonical Wnt signaling pathway.Oncotarget. 2017 Dec 12;9(3):3069-3080. doi: 10.18632/oncotarget.23149. eCollection 2018 Jan 9.
15	Brief Report: Induction of Matrix Metalloproteinase Expression by Synovial Wnt Signaling and Association With Disease Progression in Early Symptomatic Osteoarthritis.Arthritis Rheumatol. 2017 Oct;69(10):1978-1983. doi: 10.1002/art.40206. Epub 2017 Aug 29.
16	Canonical and noncanonical Wnt pathway: a comparison among normal ovary, benign ovarian tumor and ovarian cancer.Oncol Rep. 2009 Feb;21(2):313-20.
17	Evidence of a stabilizing mutation of -catenin encoded by CTNNB1 exon 3 in a large series of sporadic parathyroid adenomas.Endocrine. 2012 Dec;42(3):612-5. doi: 10.1007/s12020-012-9690-3. Epub 2012 May 11.
18	Wnt receptor Frizzled 8 is a target of ERG in prostate cancer.Prostate. 2018 Dec;78(16):1311-1320. doi: 10.1002/pros.23704. Epub 2018 Jul 26.
19	Wnt receptor gene FZD1 was associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort.Aust N Z J Psychiatry. 2020 Sep;54(9):902-908. doi: 10.1177/0004867419885443. Epub 2019 Nov 16.
20	Wnt pathway-related gene expression in inflammatory bowel disease.Dig Dis Sci. 2008 Apr;53(4):1013-9. doi: 10.1007/s10620-007-9973-3. Epub 2007 Oct 16.
21	Transcription Factors in Breast Cancer-Lessons From Recent Genomic Analyses and Therapeutic Implications.Adv Protein Chem Struct Biol. 2017;107:223-273. doi: 10.1016/bs.apcsb.2016.10.003. Epub 2016 Dec 12.
22	An essential role of the cysteine-rich domain of FZD4 in Norrin/Wnt signaling and familial exudative vitreoretinopathy.J Biol Chem. 2011 Mar 25;286(12):10210-5. doi: 10.1074/jbc.M110.194399. Epub 2010 Dec 22.
23	Promotion of epithelial-mesenchymal transition by Frizzled2 is involved in the metastasis of endometrial cancer.Oncol Rep. 2016 Aug;36(2):803-10. doi: 10.3892/or.2016.4885. Epub 2016 Jun 17.
24	The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/beta-catenin pathway.Oncogene. 2009 Jun 11;28(23):2245-56. doi: 10.1038/onc.2009.80. Epub 2009 May 4.
25	Requirement of the transcription factor YB-1 for maintaining the stemness of cancer stem cells and reverting differentiated cancer cells into cancer stem cells.Stem Cell Res Ther. 2019 Aug 2;10(1):233. doi: 10.1186/s13287-019-1360-4.
26	Intranasal wnt3a Attenuates Neuronal Apoptosis through Frz1/PIWIL1a/FOXM1 Pathway in MCAO Rats.J Neurosci. 2018 Jul 25;38(30):6787-6801. doi: 10.1523/JNEUROSCI.2352-17.2018. Epub 2018 Jun 28.
27	Resistance or sensitivity of Wilms' tumor to anti-FZD7 antibody highlights the Wnt pathway as a possible therapeutic target.Oncogene. 2011 Apr 7;30(14):1664-80. doi: 10.1038/onc.2010.549. Epub 2011 Jan 17.
28	Blood vessel epicardial substance reduces LRP6 receptor and cytoplasmic -catenin levels to modulate Wnt signaling and intestinal homeostasis.Carcinogenesis. 2019 Sep 18;40(9):1086-1098. doi: 10.1093/carcin/bgz007.
29	Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma.Int J Oncol. 2004 Nov;25(5):1337-42.
30	LRP5-linked osteoporosis-pseudoglioma syndrome mimicking isolated microphthalmia.Eur J Med Genet. 2017 Mar;60(3):200-204. doi: 10.1016/j.ejmg.2017.01.007. Epub 2017 Jan 19.
31	Frizzled-1 is down-regulated in follicular thyroid tumours and modulates growth and invasiveness.J Pathol. 2008 May;215(1):87-96. doi: 10.1002/path.2331.
32	Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer.J Pathol. 2017 Feb;241(3):350-361. doi: 10.1002/path.4841. Epub 2016 Dec 29.
33	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
34	Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
35	Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
36	Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
37	Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
38	Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
39	Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
40	Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
41	THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
42	The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling. Biochemistry. 2009 Nov 3;48(43):10267-74. doi: 10.1021/bi9009677.
43	LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
44	Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol Cancer Ther. 2005 Feb;4(2):233-41.
45	Reduced camptothecin sensitivity of estrogen receptor-positive human breast cancer cells following exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes. Environ Toxicol. 2019 Apr;34(4):401-414.
46	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.
47	Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
48	Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7516-21. doi: 10.1073/pnas.0610299104. Epub 2007 Apr 23.