Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTZ9MKK)

• DOT Name: Frizzled-9 (FZD9)
• Synonyms: Fz-9; hFz9; FzE6; CD antigen CD349
• Gene Name: FZD9
• Related Disease:
  Lung neoplasm
  Acute myelogenous leukaemia
  Gastric cancer
  leukaemia
  Leukemia
  Myelodysplastic syndrome
  Neoplasm
  Promyelocytic leukaemia
  Stomach cancer
  Neurodevelopmental disorder
  Non-small-cell lung cancer
  Bone osteosarcoma
  Osteosarcoma
• UniProt ID: FZD9_HUMAN
• Pfam ID: PF01534 ; PF01392
• Sequence:
  MAVAPLRGALLLWQLLAAGGAALEIGRFDPERGRGAAPCQAVEIPMCRGIGYNLTRMPNL
  LGHTSQGEAAAELAEFAPLVQYGCHSHLRFFLCSLYAPMCTDQVSTPIPACRPMCEQARL
  RCAPIMEQFNFGWPDSLDCARLPTRNDPHALCMEAPENATAGPAEPHKGLGMLPVAPRPA
  RPPGDLGPGAGGSGTCENPEKFQYVEKSRSCAPRCGPGVEVFWSRRDKDFALVWMAVWSA
  LCFFSTAFTVLTFLLEPHRFQYPERPIIFLSMCYNVYSLAFLIRAVAGAQSVACDQEAGA
  LYVIQEGLENTGCTLVFLLLYYFGMASSLWWVVLTLTWFLAAGKKWGHEAIEAHGSYFHM
  AAWGLPALKTIVILTLRKVAGDELTGLCYVASTDAAALTGFVLVPLSGYLVLGSSFLLTG
  FVALFHIRKIMKTGGTNTEKLEKLMVKIGVFSILYTVPATCVIVCYVYERLNMDFWRLRA
  TEQPCAAAAGPGGRRDCSLPGGSVPTVAVFMLKIFMSLVVGITSGVWVWSSKTFQTWQSL
  CYRKIAAGRARAKACRAPGSYGRGTHCHYKAPTVVLHMTKTDPSLENPTHL
• Function: Receptor for WNT2 that is 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. Plays a role in neuromuscular junction (NMJ) assembly by negatively regulating the clustering of acetylcholine receptors (AChR) through the beta-catenin canonical signaling pathway. May play a role in neural progenitor cells (NPCs) viability through the beta-catenin canonical signaling pathway by negatively regulating cell cycle arrest leading to inhibition of neuron apoptotic process. During hippocampal development, regulates neuroblast proliferation and apoptotic cell death. Controls bone formation through non canonical Wnt signaling mediated via ISG15. Positively regulates bone regeneration through non canonical Wnt signaling.
• Tissue Specificity: Expressed predominantly in adult and fetal brain, testis, eye, skeletal muscle and kidney. Moderately expressed in pancreas, thyroid, adrenal cortex, small intestine and stomach. Detected in fetal liver and kidney. Expressed in neural progenitor cells .
• 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)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung neoplasm	DISVARNB	Definitive	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Posttranslational Modification	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
leukaemia	DISS7D1V	Strong	Genetic Variation	[2]
Leukemia	DISNAKFL	Strong	Genetic Variation	[2]
Myelodysplastic syndrome	DISYHNUI	Strong	Posttranslational Modification	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Promyelocytic leukaemia	DISYGG13	Strong	Posttranslational Modification	[2]
Stomach cancer	DISKIJSX	Strong	Biomarker	[3]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[5]
Non-small-cell lung cancer	DIS5Y6R9	Disputed	Biomarker	[6]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[7]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[7]

1 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 Frizzled-9 (FZD9).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Frizzled-9 (FZD9).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Frizzled-9 (FZD9).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Frizzled-9 (FZD9).	[11]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Frizzled-9 (FZD9).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Frizzled-9 (FZD9).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the expression of Frizzled-9 (FZD9).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Frizzled-9 (FZD9).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Frizzled-9 (FZD9).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Frizzled-9 (FZD9).	[17]

References

• [1] Prostacyclin reverses the cigarette smoke-induced decrease in pulmonary Frizzled 9 expression through miR-31.Sci Rep. 2016 Jun 24;6:28519. doi: 10.1038/srep28519.
• [2] Methylation status of the promoter region of the human frizzled 9 gene in acute myeloid leukemia.Mol Med Rep. 2016 Aug;14(2):1339-44. doi: 10.3892/mmr.2016.5387. Epub 2016 Jun 10.
• [3] Expression profiles of 10 members of Frizzled gene family in human gastric cancer.Int J Oncol. 2001 Oct;19(4):767-71. doi: 10.3892/ijo.19.4.767.
• [4] Aberrant DNA methylation is a dominant mechanism in MDS progression to AML.Blood. 2009 Feb 5;113(6):1315-25. doi: 10.1182/blood-2008-06-163246. Epub 2008 Oct 2.
• [5] Frizzled 9 knock-out mice have abnormal B-cell development.Blood. 2005 Mar 15;105(6):2487-94. doi: 10.1182/blood-2004-06-2334. Epub 2004 Nov 30.
• [6] Restoration of Wnt-7a expression reverses non-small cell lung cancer cellular transformation through frizzled-9-mediated growth inhibition and promotion of cell differentiation.J Biol Chem. 2005 May 20;280(20):19625-34. doi: 10.1074/jbc.M409392200. Epub 2005 Feb 10.
• [7] Involvement of c-Fos in cell proliferation, migration, and invasion in osteosarcoma cells accompanied by altered expression of Wnt2 and Fzd9.PLoS One. 2017 Jun 30;12(6):e0180558. doi: 10.1371/journal.pone.0180558. eCollection 2017.
• [8] 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.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [12] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene. BMC Genomics. 2011 Jun 29;12:333.
• [15] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [16] 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.
• [17] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.