Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKTMVC4)

• DOT Name: F-box only protein 28 (FBXO28)
• Gene Name: FBXO28
• Related Disease:
  Developmental and epileptic encephalopathy 100
  Intellectual disability
  Neoplasm
  Schizophrenia
  Breast cancer
  Breast carcinoma
  Non-insulin dependent diabetes
  Type-1/2 diabetes
• UniProt ID: FBX28_HUMAN
• Pfam ID: PF00646
• Sequence:
  MAAAAEERMAEEGGGGQGDGGSSLASGSTQRQPPPPAPQHPQPGSQALPAPALAPDQLPQ
  NNTLVALPIVAIENILSFMSYDEISQLRLVCKRMDLVCQRMLNQGFLKVERYHNLCQKQV
  KAQLPRRESERRNHSLARHADILAAVETRLSLLNMTFMKYVDSNLCCFIPGKVIDEIYRV
  LRYVNSTRAPQRAHEVLQELRDISSMAMEYFDEKIVPILKRKLPGSDVSGRLMGSPPVPG
  PSAALTTMQLFSKQNPSRQEVTKLQQQVKTNGAGVTVLRREISELRTKVQEQQKQLQDQD
  QKLLEQTQIIGEQNARLAELERKLREVMESAVGNSSGSGQNEESPRKRKKATEAIDSLRK
  SKRLRNRK
• Function: Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy 100	DISMK76R	Strong	Autosomal dominant	[1]
Intellectual disability	DISMBNXP	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[2]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[4]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[4]

8 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 28 (FBXO28).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of F-box only protein 28 (FBXO28).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of F-box only protein 28 (FBXO28).	[7]
Selenium	DM25CGV	Approved	Selenium decreases the expression of F-box only protein 28 (FBXO28).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of F-box only protein 28 (FBXO28).	[10]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of F-box only protein 28 (FBXO28).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of F-box only protein 28 (FBXO28).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of F-box only protein 28 (FBXO28).	[14]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of F-box only protein 28 (FBXO28).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of F-box only protein 28 (FBXO28).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of F-box only protein 28 (FBXO28).	[9]

References

• [1] Refinement of the critical region of 1q41q42 microdeletion syndrome identifies FBXO28 as a candidate causative gene for intellectual disability and seizures. Am J Med Genet A. 2014 Feb;164A(2):441-8. doi: 10.1002/ajmg.a.36320. Epub 2013 Dec 19.
• [2] TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.Oncotarget. 2017 Mar 14;8(11):18381-18398. doi: 10.18632/oncotarget.15110.
• [3] A kernel machine method for detecting higher order interactions in multimodal datasets: Application to schizophrenia.J Neurosci Methods. 2018 Nov 1;309:161-174. doi: 10.1016/j.jneumeth.2018.08.027. Epub 2018 Sep 2.
• [4] An SCF(FBXO28) E3 Ligase Protects Pancreatic -Cells from Apoptosis.Int J Mol Sci. 2018 Mar 24;19(4):975. doi: 10.3390/ijms19040975.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] 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.
• [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] 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.
• [10] Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen. Cancer Genet Cytogenet. 2006 Apr 15;166(2):130-8. doi: 10.1016/j.cancergencyto.2005.09.012.
• [11] 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.
• [12] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.