Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0WGWZS)

• DOT Name: Fizzy-related protein homolog (FZR1)
• Synonyms: Fzr; CDC20-like protein 1; Cdh1/Hct1 homolog; hCDH1
• Gene Name: FZR1
• Related Disease:
  Acute leukaemia
  Acute myelogenous leukaemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Developmental and epileptic encephalopathy 109
  Head-neck squamous cell carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Isolated congenital microcephaly
  Kabuki syndrome
  Medulloblastoma
  Neoplasm
  Neuralgia
  Neurodevelopmental disorder
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Gastric cancer
  Stomach cancer
  OPTN-related open angle glaucoma
• UniProt ID: FZR1_HUMAN
• PDB ID: 4UI9; 5L9T; 5L9U; 7QE7; 8TAR; 8TAU
• Pfam ID: PF12894 ; PF00400
• Sequence:
  MDQDYERRLLRQIVIQNENTMPRVTEMRRTLTPASSPVSSPSKHGDRFIPSRAGANWSVN
  FHRINENEKSPSQNRKAKDATSDNGKDGLAYSALLKNELLGAGIEKVQDPQTEDRRLQPS
  TPEKKGLFTYSLSTKRSSPDDGNDVSPYSLSPVSNKSQKLLRSPRKPTRKISKIPFKVLD
  APELQDDFYLNLVDWSSLNVLSVGLGTCVYLWSACTSQVTRLCDLSVEGDSVTSVGWSER
  GNLVAVGTHKGFVQIWDAAAGKKLSMLEGHTARVGALAWNAEQLSSGSRDRMILQRDIRT
  PPLQSERRLQGHRQEVCGLKWSTDHQLLASGGNDNKLLVWNHSSLSPVQQYTEHLAAVKA
  IAWSPHQHGLLASGGGTADRCIRFWNTLTGQPLQCIDTGSQVCNLAWSKHANELVSTHGY
  SQNQILVWKYPSLTQVAKLTGHSYRVLYLAMSPDGEAIVTGAGDETLRFWNVFSKTRSTK
  VKWESVSVLNLFTRIR
• Function: Substrate-specific adapter for the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin-protein ligase complex. Associates with the APC/C in late mitosis, in replacement of CDC20, and activates the APC/C during anaphase and telophase. The APC/C remains active in degrading substrates to ensure that positive regulators of the cell cycle do not accumulate prematurely. At the G1/S transition FZR1 is phosphorylated, leading to its dissociation from the APC/C. Following DNA damage, it is required for the G2 DNA damage checkpoint: its dephosphorylation and reassociation with the APC/C leads to the ubiquitination of PLK1, preventing entry into mitosis. Acts as an adapter for APC/C to target the DNA-end resection factor RBBP8/CtIP for ubiquitination and subsequent proteasomal degradation. Through the regulation of RBBP8/CtIP protein turnover, may play a role in DNA damage response, favoring DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR).
• Tissue Specificity: Isoform 2 is expressed at high levels in heart, liver, spleen and some cancer cell lines whereas isoform 3 is expressed only at low levels in these tissues.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Ubiquitin mediated proteolysis (hsa04120)
  Progesterone-mediated oocyte maturation (hsa04914)
• Reactome Pathway:
  SCF-beta-TrCP mediated degradation of Emi1 (R-HSA-174113)
  APC/C (R-HSA-174178)
  Conversion from APC/C (R-HSA-176407)
  Regulation of APC/C activators between G1/S and early anaphase (R-HSA-176408)
  Phosphorylation of Emi1 (R-HSA-176417)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  Assembly of the pre-replicative complex (R-HSA-68867)
  CDK-mediated phosphorylation and removal of Cdc6 (R-HSA-69017)
  Cyclin A (R-HSA-69656)
  Transcriptional Regulation by VENTX (R-HSA-8853884)
  Aberrant regulation of mitotic exit in cancer due to RB1 defects (R-HSA-9687136)
  Antigen processing (R-HSA-983168)
  Autodegradation of Cdh1 by Cdh1 (R-HSA-174084)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Altered Expression	[6]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[6]
Developmental and epileptic encephalopathy 109	DIS2HX2Z	Strong	Autosomal dominant	[7]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[8]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Genetic Variation	[9]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[7]
Kabuki syndrome	DISZN97H	Strong	Genetic Variation	[3]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Neuralgia	DISWO58J	Strong	Biomarker	[12]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[7]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[13]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[14]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[14]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[15]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[15]
OPTN-related open angle glaucoma	DISDR98A	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Fizzy-related protein homolog (FZR1).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Fizzy-related protein homolog (FZR1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Fizzy-related protein homolog (FZR1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Fizzy-related protein homolog (FZR1).	[18]
Selenium	DM25CGV	Approved	Selenium increases the expression of Fizzy-related protein homolog (FZR1).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Fizzy-related protein homolog (FZR1).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Fizzy-related protein homolog (FZR1).	[20]

References

• [1] FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia.Blood. 2017 Apr 6;129(14):1958-1968. doi: 10.1182/blood-2016-07-726216. Epub 2017 Jan 31.
• [2] CDH1 (E-cadherin) expression independently affects clinical outcome in acute myeloid leukemia with normal cytogenetics.Clin Chem Lab Med. 2017 Jan 1;55(1):123-131. doi: 10.1515/cclm-2016-0205.
• [3] A comparative analysis of KMT2D missense variants in Kabuki syndrome, cancers and the general population.J Hum Genet. 2019 Feb;64(2):161-170. doi: 10.1038/s10038-018-0536-6. Epub 2018 Nov 20.
• [4] Differences and molecular immunohistochemical parameters in the subtypes of infiltrating ductal breast cancer.Am J Clin Pathol. 2008 Sep;130(3):414-24. doi: 10.1309/J3QV9763DYPV338D.
• [5] Dissection of the APCCdh1-Skp2 cascade in breast cancer.Clin Cancer Res. 2008 Apr 1;14(7):1966-75. doi: 10.1158/1078-0432.CCR-07-1585.
• [6] LSD1-mediated epigenetic modification contributes to proliferation and metastasis of colon cancer.Br J Cancer. 2013 Aug 20;109(4):994-1003. doi: 10.1038/bjc.2013.364. Epub 2013 Jul 30.
• [7] A novel human Cdh1 mutation impairs anaphase promoting complex/cyclosome activity resulting in microcephaly, psychomotor retardation, and epilepsy. J Neurochem. 2019 Oct;151(1):103-115. doi: 10.1111/jnc.14828. Epub 2019 Aug 22.
• [8] Restoration of E-cadherin expression by selective Cox-2 inhibition and the clinical relevance of the epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma.J Exp Clin Cancer Res. 2014 May 10;33(1):40. doi: 10.1186/1756-9966-33-40.
• [9] Molecular pathology of familial gastric cancer, with an emphasis on hereditary diffuse gastric cancer.J Clin Pathol. 2008 Jan;61(1):25-30. doi: 10.1136/jcp.2006.043679. Epub 2007 May 18.
• [10] Biological characterization of the UW402, UW473, ONS-76 and DAOY pediatric medulloblastoma cell lines.Cytotechnology. 2019 Oct;71(5):893-903. doi: 10.1007/s10616-019-00332-3. Epub 2019 Jul 26.
• [11] Anaphase-Promoting Complex Adaptor FZR1/CDH1 Blocks BRAF Signaling Both by Targeting BRAF for Proteolytic Degradation and by Disrupting BRAF Dimerization.Cancer Discov. 2017 Apr;7(4):356-358. doi: 10.1158/2159-8290.CD-17-0172.
• [12] An integrated review on new targets in the treatment of neuropathic pain.Korean J Physiol Pharmacol. 2019 Jan;23(1):1-20. doi: 10.4196/kjpp.2019.23.1.1. Epub 2018 Dec 26.
• [13] Identification of the APC/C co-factor FZR1 as a novel therapeutic target for multiple myeloma.Oncotarget. 2016 Oct 25;7(43):70481-70493. doi: 10.18632/oncotarget.12026.
• [14] E-cadherin gene 3'-UTR C/T polymorphism is associated with prostate cancer.Urol Int. 2005;75(4):350-3. doi: 10.1159/000089173.
• [15] Digital PCR identifies changes in CDH1 (E-cadherin) transcription pattern in intestinal-type gastric cancer.Oncotarget. 2017 Mar 21;8(12):18811-18820. doi: 10.18632/oncotarget.13401.
• [16] Association of E-cadherin gene 3'-UTR C/T polymorphism with primary open angle glaucoma.Ophthalmic Res. 2006;38(1):44-8. doi: 10.1159/000089523. Epub 2005 Nov 7.
• [17] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [20] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] 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.