Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFY2SBE)

• DOT Name: F-box only protein 3 (FBXO3)
• Gene Name: FBXO3
• UniProt ID: FBX3_HUMAN
• PDB ID: 5HDW
• Pfam ID: PF04379 ; PF12937 ; PF09346
• Sequence:
  MAAMETETAPLTLESLPTDPLLLILSFLDYRDLINCCYVSRRLSQLSSHDPLWRRHCKKY
  WLISEEEKTQKNQCWKSLFIDTYSDVGRYIDHYAAIKKAWDDLKKYLEPRCPRMVLSLKE
  GAREEDLDAVEAQIGCKLPDDYRCSYRIHNGQKLVVPGLLGSMALSNHYRSEDLLDVDTA
  AGGFQQRQGLKYCLPLTFCIHTGLSQYIAVEAAEGRNKNEVFYQCPDQMARNPAAIDMFI
  IGATFTDWFTSYVKNVVSGGFPIIRDQIFRYVHDPECVATTGDITVSVSTSFLPELSSVH
  PPHYFFTYRIRIEMSKDALPEKACQLDSRYWRITNAKGDVEEVQGPGVVGEFPIISPGRV
  YEYTSCTTFSTTSGYMEGYYTFHFLYFKDKIFNVAIPRFHMACPTFRVSIARLEMGPDEY
  EEMEEEEEEEEEEDEDDDSADMDESDEDDEEERRRRVFDVPIRRRRCSRLF
• Function: Substrate recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex, SCF(FBXO3), which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Mediates the ubiquitination of HIPK2 and probably that of EP300, leading to rapid degradation by the proteasome. In the presence of PML, HIPK2 ubiquitination still occurs, but degradation is prevented. PML, HIPK2 and FBXO3 may act synergically to activate p53/TP53-dependent transactivation. The SCF(FBXO3) also acts as a regulator of inflammation by mediating ubiquitination and degradation of FBXL2 in response to lipopolysaccharide (LPS). The SCF(FBXO3) complex specifically recognizes FBXL2 phosphorylated at 'Thr-404' and promotes its ubiquitination.

Molecular Interaction Atlas (MIA) of This DOT

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 only protein 3 (FBXO3).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of F-box only protein 3 (FBXO3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of F-box only protein 3 (FBXO3).	[14]

12 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 3 (FBXO3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of F-box only protein 3 (FBXO3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of F-box only protein 3 (FBXO3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of F-box only protein 3 (FBXO3).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of F-box only protein 3 (FBXO3).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of F-box only protein 3 (FBXO3).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of F-box only protein 3 (FBXO3).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of F-box only protein 3 (FBXO3).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of F-box only protein 3 (FBXO3).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of F-box only protein 3 (FBXO3).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of F-box only protein 3 (FBXO3).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of F-box only protein 3 (FBXO3).	[15]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [8] 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.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.