Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF3677S)

• DOT Name: F-box only protein 2 (FBXO2)
• Gene Name: FBXO2
• Related Disease:
  Parkinson disease
  Alzheimer disease
  Epstein barr virus infection
  Gastric cancer
  Hyperglycemia
  Rheumatoid arthritis
  Stomach cancer
• UniProt ID: FBX2_HUMAN
• Pfam ID: PF12937 ; PF04300
• Sequence:
  MDGDGDPESVGQPEEASPEEQPEEASAEEERPEDQQEEEAAAAAAYLDELPEPLLLRVLA
  ALPAAELVQACRLVCLRWKELVDGAPLWLLKCQQEGLVPEGGVEEERDHWQQFYFLSKRR
  RNLLRNPCGEEDLEGWCDVEHGGDGWRVEELPGDSGVEFTHDESVKKYFASSFEWCRKAQ
  VIDLQAEGYWEELLDTTQPAIVVKDWYSGRSDAGCLYELTVKLLSEHENVLAEFSSGQVA
  VPQDSDGGGWMEISHTFTDYGPGVRFVRFEHGGQDSVYWKGWFGARVTNSSVWVEP
• Function: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Involved in the endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins by recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation. Prevents formation of cytosolic aggregates of unfolded glycoproteins that have been retrotranslocated into the cytosol. Able to recognize and bind denatured glycoproteins, preferentially those of the high-mannose type.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Definitive	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Epstein barr virus infection	DISOO0WT	Limited	Altered Expression	[3]
Gastric cancer	DISXGOUK	Limited	Biomarker	[4]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[5]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[6]
Stomach cancer	DISKIJSX	Limited	Biomarker	[4]

2 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 F-box only protein 2 (FBXO2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of F-box only protein 2 (FBXO2).	[23]

19 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 only protein 2 (FBXO2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of F-box only protein 2 (FBXO2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of F-box only protein 2 (FBXO2).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of F-box only protein 2 (FBXO2).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of F-box only protein 2 (FBXO2).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of F-box only protein 2 (FBXO2).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of F-box only protein 2 (FBXO2).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of F-box only protein 2 (FBXO2).	[15]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of F-box only protein 2 (FBXO2).	[16]
Selenium	DM25CGV	Approved	Selenium increases the expression of F-box only protein 2 (FBXO2).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of F-box only protein 2 (FBXO2).	[18]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of F-box only protein 2 (FBXO2).	[19]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of F-box only protein 2 (FBXO2).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of F-box only protein 2 (FBXO2).	[18]
Rigosertib	DMOSTXF	Phase 3	Rigosertib affects the expression of F-box only protein 2 (FBXO2).	[21]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of F-box only protein 2 (FBXO2).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of F-box only protein 2 (FBXO2).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of F-box only protein 2 (FBXO2).	[25]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of F-box only protein 2 (FBXO2).	[26]

References

• [1] Genetic Analysis of FBXO2, FBXO6, FBXO12, and FBXO41 Variants in Han Chinese Patients with Sporadic Parkinson's Disease.Neurosci Bull. 2017 Oct;33(5):510-514. doi: 10.1007/s12264-017-0122-5. Epub 2017 Mar 24.
• [2] SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer's disease amyloidosis and improves synaptic function.Aging Cell. 2010 Dec;9(6):1018-31. doi: 10.1111/j.1474-9726.2010.00632.x. Epub 2010 Oct 29.
• [3] Epstein-Barr virus activates F-box protein FBXO2 to limit viral infectivity by targeting glycoprotein B for degradation.PLoS Pathog. 2018 Jul 27;14(7):e1007208. doi: 10.1371/journal.ppat.1007208. eCollection 2018 Jul.
• [4] FBXO2, a novel marker for metastasis in human gastric cancer.Biochem Biophys Res Commun. 2018 Jan 15;495(3):2158-2164. doi: 10.1016/j.bbrc.2017.12.097. Epub 2017 Dec 18.
• [5] Aberrant Expression of FBXO2 Disrupts Glucose Homeostasis Through Ubiquitin-Mediated Degradation of Insulin Receptor in Obese Mice.Diabetes. 2017 Mar;66(3):689-698. doi: 10.2337/db16-1104. Epub 2016 Dec 8.
• [6] Novel approach to identifying autoantibodies in rheumatoid synovitis with a biotinylated human autoantigen library and the enzyme-labeled antigen method.J Immunol Methods. 2013 Jan 31;387(1-2):57-70. doi: 10.1016/j.jim.2012.09.011. Epub 2012 Oct 5.
• [7] 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.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] 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.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] 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.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [20] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [21] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [22] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [23] 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.
• [24] 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.
• [25] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [26] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.