Details of Drug Off-Target (DOT)

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

• DOT Name: Proto-oncogene Wnt-1
• Synonyms: Proto-oncogene Int-1 homolog
• Gene Name: WNT1
• Related Disease:
  Idiopathic juvenile osteoporosis
  Osteogenesis imperfecta type 15
  Osteogenesis imperfecta type 3
  Osteogenesis imperfecta type 4
• UniProt ID: WNT1_HUMAN
• Pfam ID: PF00110
• Sequence:
  MGLWALLPGWVSATLLLALAALPAALAANSSGRWWGIVNVASSTNLLTDSKSLQLVLEPS
  LQLLSRKQRRLIRQNPGILHSVSGGLQSAVRECKWQFRNRRWNCPTAPGPHLFGKIVNRG
  CRETAFIFAITSAGVTHSVARSCSEGSIESCTCDYRRRGPGGPDWHWGGCSDNIDFGRLF
  GREFVDSGEKGRDLRFLMNLHNNEAGRTTVFSEMRQECKCHGMSGSCTVRTCWMRLPTLR
  AVGDVLRDRFDGASRVLYGNRGSNRASRAELLRLEPEDPAHKPPSPHDLVYFEKSPNFCT
  YSGRLGTAGTAGRACNSSSPALDGCELLCCGRGHRTRTQRVTERCNCTFHWCCHVSCRNC
  THTRVLHECL
• Function: Ligand for members of the frizzled family of seven transmembrane receptors (Probable). Acts in the canonical Wnt signaling pathway by promoting beta-catenin-dependent transcriptional activation. In some developmental processes, is also a ligand for the coreceptor RYK, thus triggering Wnt signaling. Plays an essential role in the development of the embryonic brain and central nervous system (CNS). Has a role in osteoblast function, bone development and bone homeostasis.
• 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)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Basal cell carcinoma (hsa05217)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  WNT ligand biogenesis and trafficking (R-HSA-3238698)
  Class B/2 (Secretin family receptors) (R-HSA-373080)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  PCP/CE pathway (R-HSA-4086400)
  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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Idiopathic juvenile osteoporosis	DISNYIPM	Strong	Autosomal dominant	[1]
Osteogenesis imperfecta type 15	DIS9ICS7	Strong	Autosomal recessive	[2]
Osteogenesis imperfecta type 3	DISFJVSJ	Supportive	Autosomal dominant	[3]
Osteogenesis imperfecta type 4	DIS8S46L	Supportive	Autosomal dominant	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	Proto-oncogene Wnt-1 increases the Leiomyoma ADR of Progesterone.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Proto-oncogene Wnt-1.	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Proto-oncogene Wnt-1.	[6]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Proto-oncogene Wnt-1.	[7]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Proto-oncogene Wnt-1.	[9]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Proto-oncogene Wnt-1.	[10]
Linalool	DMGZQ5P	Investigative	Linalool increases the expression of Proto-oncogene Wnt-1.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Proto-oncogene Wnt-1.	[8]

References

• [1] Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet. 2013 Apr 4;92(4):565-74. doi: 10.1016/j.ajhg.2013.02.010. Epub 2013 Mar 14.
• [2] Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development. Nature. 1990 Aug 30;346(6287):847-50. doi: 10.1038/346847a0.
• [3] WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta. Am J Hum Genet. 2013 Apr 4;92(4):590-7. doi: 10.1016/j.ajhg.2013.02.009. Epub 2013 Mar 14.
• [4] Mutations in WNT1 are a cause of osteogenesis imperfecta. J Med Genet. 2013 May;50(5):345-8. doi: 10.1136/jmedgenet-2013-101567. Epub 2013 Feb 23.
• [5] Effects of valproic acid on gene expression during human embryonic stem cell differentiation into neurons. J Toxicol Sci. 2014 Jun;39(3):383-90. doi: 10.2131/jts.39.383.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] The anthelmintic drug niclosamide induces GSK--mediated -catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability and suppress pancreatic cancer progression. Cell Death Dis. 2022 Feb 3;13(2):112. doi: 10.1038/s41419-022-04573-7.
• [8] 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.
• [9] Ochratoxin A induces epithelial-to-mesenchymal transition and renal fibrosis through TGF-/Smad2/3 and Wnt1/-catenin signaling pathways in vitro and in vivo. Arch Toxicol. 2020 Sep;94(9):3329-3342. doi: 10.1007/s00204-020-02829-9. Epub 2020 Jul 2.
• [10] Aberrant Wnt/Beta-Catenin Pathway Activation in Dialysate-Induced Peritoneal Fibrosis. Front Pharmacol. 2017 Oct 30;8:774. doi: 10.3389/fphar.2017.00774. eCollection 2017.
• [11] Linalool preferentially induces robust apoptosis of a variety of leukemia cells via upregulating p53 and cyclin-dependent kinase inhibitors. Toxicology. 2010 Jan 31;268(1-2):19-24. doi: 10.1016/j.tox.2009.11.013. Epub 2009 Nov 14.
• [12] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.