Details of Drug Off-Target (DOT)

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

• DOT Name: F-box/WD repeat-containing protein 2 (FBXW2)
• Synonyms: F-box and WD-40 domain-containing protein 2; Protein MD6
• Gene Name: FBXW2
• Related Disease:
  Lung cancer
  Lung carcinoma
  Neoplasm
• UniProt ID: FBXW2_HUMAN
• Pfam ID: PF12937 ; PF00400
• Sequence:
  MERKDFETWLDNISVTFLSLTDLQKNETLDHLISLSGAVQLRHLSNNLETLLKRDFLKLL
  PLELSFYLLKWLDPQTLLTCCLVSKQWNKVISACTEVWQTACKNLGWQIDDSVQDALHWK
  KVYLKAILRMKQLEDHEAFETSSLIGHSARVYALYYKDGLLCTGSDDLSAKLWDVSTGQC
  VYGIQTHTCAAVKFDEQKLVTGSFDNTVACWEWSSGARTQHFRGHTGAVFSVDYNDELDI
  LVSGSADFTVKVWALSAGTCLNTLTGHTEWVTKVVLQKCKVKSLLHSPGDYILLSADKYE
  IKIWPIGREINCKCLKTLSVSEDRSICLQPRLHFDGKYIVCSSALGLYQWDFASYDILRV
  IKTPEIANLALLGFGDIFALLFDNRYLYIMDLRTESLISRWPLPEYRKSKRGSSFLAGEA
  SWLNGLDGHNDTGLVFATSMPDHSIHLVLWKEHG
• Function: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  Antigen processing (R-HSA-983168)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]

3 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 F-box/WD repeat-containing protein 2 (FBXW2).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of F-box/WD repeat-containing protein 2 (FBXW2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of F-box/WD repeat-containing protein 2 (FBXW2).	[9]

6 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 F-box/WD repeat-containing protein 2 (FBXW2).	[3]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of F-box/WD repeat-containing protein 2 (FBXW2).	[5]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of F-box/WD repeat-containing protein 2 (FBXW2).	[6]
Phenol	DM1QSM3	Phase 2/3	Phenol decreases the expression of F-box/WD repeat-containing protein 2 (FBXW2).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of F-box/WD repeat-containing protein 2 (FBXW2).	[8]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of F-box/WD repeat-containing protein 2 (FBXW2).	[10]

References

• [1] FBXW2 suppresses migration and invasion of lung cancer cells via promoting -catenin ubiquitylation and degradation.Nat Commun. 2019 Mar 27;10(1):1382. doi: 10.1038/s41467-019-09289-5.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [6] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [7] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [8] 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.
• [9] 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.
• [10] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.