Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT58MKP3)

• DOT Name: F-box only protein 6 (FBXO6)
• Synonyms: F-box protein that recognizes sugar chains 2; F-box/G-domain protein 2
• Gene Name: FBXO6
• Related Disease:
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Stevens-Johnson syndrome
  Toxic epidermal necrolysis
  Asthma
• UniProt ID: FBX6_HUMAN
• Pfam ID: PF12937 ; PF04300
• Sequence:
  MDAPHSKAALDSINELPENILLELFTHVPARQLLLNCRLVCSLWRDLIDLMTLWKRKCLR
  EGFITKDWDQPVADWKIFYFLRSLHRNLLRNPCAEEDMFAWQIDFNGGDRWKVESLPGAH
  GTDFPDPKVKKYFVTSYEMCLKSQLVDLVAEGYWEELLDTFRPDIVVKDWFAARADCGCT
  YQLKVQLASADYFVLASFEPPPVTIQQWNNATWTEVSYTFSDYPRGVRYILFQHGGRDTQ
  YWAGWYGPRVTNSSIVVSPKMTRNQASSEAQPGQKHGQEEAAQSPYRAVVQIF
• Function: Substrate-recognition component of some SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complexes. Involved in 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. Able to recognize and bind denatured glycoproteins, which are modified with not only high-mannose but also complex-type oligosaccharides. Also recognizes sulfated glycans. Also involved in DNA damage response by specifically recognizing activated CHEK1 (phosphorylated on 'Ser-345'), promoting its ubiquitination and degradation. Ubiquitination of CHEK1 is required to ensure that activated CHEK1 does not accumulate as cells progress through S phase, or when replication forks encounter transient impediments during normal DNA replication.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• 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

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Altered Expression	[2]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Stevens-Johnson syndrome	DISZG4YX	Strong	Biomarker	[4]
Toxic epidermal necrolysis	DISIWPFR	Strong	Biomarker	[4]
Asthma	DISW9QNS	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of F-box only protein 6 (FBXO6).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of F-box only protein 6 (FBXO6).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of F-box only protein 6 (FBXO6).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of F-box only protein 6 (FBXO6).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of F-box only protein 6 (FBXO6).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of F-box only protein 6 (FBXO6).	[11]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of F-box only protein 6 (FBXO6).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of F-box only protein 6 (FBXO6).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of F-box only protein 6 (FBXO6).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of F-box only protein 6 (FBXO6).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of F-box only protein 6 (FBXO6).	[17]

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 decreases the methylation of F-box only protein 6 (FBXO6).	[13]

References

• [1] The F box protein Fbx6 regulates Chk1 stability and cellular sensitivity to replication stress.Mol Cell. 2009 Aug 28;35(4):442-53. doi: 10.1016/j.molcel.2009.06.030.
• [2] Noncanonical Role of FBXO6 in Regulating Antiviral Immunity.J Immunol. 2019 Aug 15;203(4):1012-1020. doi: 10.4049/jimmunol.1801557. Epub 2019 Jul 15.
• [3] Fbxo6 confers drug-sensitization to cisplatin via inhibiting the activation of Chk1 in non-small cell lung cancer.FEBS Lett. 2019 Jul;593(14):1827-1836. doi: 10.1002/1873-3468.13461. Epub 2019 Jun 7.
• [4] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [5] Identification of differentially expressed genes associated with asthma in children based on the bioanalysis of the regulatory network.Mol Med Rep. 2018 Aug;18(2):2153-2163. doi: 10.3892/mmr.2018.9205. Epub 2018 Jun 22.
• [6] 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.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [13] 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.
• [14] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [15] 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.
• [16] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.