Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDFA7F4)

• DOT Name: F-box only protein 25 (FBXO25)
• Gene Name: FBXO25
• Related Disease:
  Mantle cell lymphoma
  Neoplasm
  Moyamoya disease
  Type-1/2 diabetes
• UniProt ID: FBX25_HUMAN
• Sequence:
  MPFLGQDWRSPGWSWIKTEDGWKRCESCSQKLERENNRCNISHSIILNSEDGEIFNNEEH
  EYASKKRKKDHFRNDTNTQSFYREKWIYVHKESTKERHGYCTLGEAFNRLDFSSAIQDIR
  RFNYVVKLLQLIAKSQLTSLSGVAQKNYFNILDKIVQKVLDDHHNPRLIKDLLQDLSSTL
  CILIRGVGKSVLVGNINIWICRLETILAWQQQLQDLQMTKQVNNGLTLSDLPLHMLNNIL
  YRFSDGWDIITLGQVTPTLYMLSEDRQLWKKLCQYHFAEKQFCRHLILSEKGHIEWKLMY
  FALQKHYPAKEQYGDTLHFCRHCSILFWKDYHLALLFKDSGHPCTAADPDSCFTPVSPQH
  FIDLFKF
• Function: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. May play a role in accumulation of expanded polyglutamine (polyQ) protein huntingtin (HTT).
• Tissue Specificity: Expressed in all brain tissue observed.
• KEGG Pathway: FoxO sig.ling pathway (hsa04068)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Moyamoya disease	DISO62CA	moderate	Genetic Variation	[2]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[3]

1 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 25 (FBXO25).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of F-box only protein 25 (FBXO25).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of F-box only protein 25 (FBXO25).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of F-box only protein 25 (FBXO25).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of F-box only protein 25 (FBXO25).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of F-box only protein 25 (FBXO25).	[9]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of F-box only protein 25 (FBXO25).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of F-box only protein 25 (FBXO25).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of F-box only protein 25 (FBXO25).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of F-box only protein 25 (FBXO25).	[13]

References

• [1] Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis.Nat Med. 2014 Dec;20(12):1401-9. doi: 10.1038/nm.3740. Epub 2014 Nov 24.
• [2] Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study.Stroke. 2018 Jan;49(1):11-18. doi: 10.1161/STROKEAHA.117.017430.
• [3] FBXO25, an F-box protein homologue of atrogin-1, is not induced in atrophying muscle.Biochim Biophys Acta. 2006 Jun;1760(6):966-72. doi: 10.1016/j.bbagen.2006.03.020. Epub 2006 Apr 4.
• [4] 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.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] 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.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [11] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.