Details of Drug Off-Target (DOT)

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

• DOT Name: F-box/LRR-repeat protein 4 (FBXL4)
• Synonyms: F-box and leucine-rich repeat protein 4; F-box protein FBL4/FBL5
• Gene Name: FBXL4
• Related Disease:
  Lactic acidosis
  Leigh syndrome
  Cardiomyopathy
  Major depressive disorder
  Mitochondrial DNA depletion syndrome 13
  Mitochondrial encephalomyopathy
  Neuromuscular disease
  Mitochondrial DNA depletion syndrome
  Advanced cancer
  Mitochondrial disease
  Prostate cancer
  Prostate carcinoma
• UniProt ID: FBXL4_HUMAN
• Pfam ID: PF12937
• Sequence:
  MSPVFPMLTVLTMFYYICLRRRARTATRGEMMNTHRAIESNSQTSPLNAEVVQYAKEVVD
  FSSHYGSENSMSYTMWNLAGVPNVFPSSGDFTQTAVFRTYGTWWDQCPSASLPFKRTPPN
  FQSQDYVELTFEQQVYPTAVHVLETYHPGAVIRILACSANPYSPNPPAEVRWEILWSERP
  TKVNASQARQFKPCIKQINFPTNLIRLEVNSSLLEYYTELDAVVLHGVKDKPVLSLKTSL
  IDMNDIEDDAYAEKDGCGMDSLNKKFSSAVLGEGPNNGYFDKLPYELIQLILNHLTLPDL
  CRLAQTCKLLSQHCCDPLQYIHLNLQPYWAKLDDTSLEFLQSRCTLVQWLNLSWTGNRGF
  ISVAGFSRFLKVCGSELVRLELSCSHFLNETCLEVISEMCPNLQALNLSSCDKLPPQAFN
  HIAKLCSLKRLVLYRTKVEQTALLSILNFCSELQHLSLGSCVMIEDYDVIASMIGAKCKK
  LRTLDLWRCKNITENGIAELASGCPLLEELDLGWCPTLQSSTGCFTRLAHQLPNLQKLFL
  TANRSVCDTDIDELACNCTRLQQLDILGTRMVSPASLRKLLESCKDLSLLDVSFCSQIDN
  RAVLELNASFPKVFIKKSFTQ
• Tissue Specificity: Expressed in heart, kidney, liver, lung, pancreas, and placenta, but not in skeletal muscle.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lactic acidosis	DISZI1ZK	Definitive	Genetic Variation	[1]
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[2]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[3]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[4]
Mitochondrial DNA depletion syndrome 13	DISMJ0SB	Strong	Autosomal recessive	[5]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Genetic Variation	[6]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[7]
Mitochondrial DNA depletion syndrome	DISIGZSM	Disputed	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[8]
Mitochondrial disease	DISKAHA3	Limited	Biomarker	[1]
Prostate cancer	DISF190Y	Limited	Biomarker	[8]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of F-box/LRR-repeat protein 4 (FBXL4).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of F-box/LRR-repeat protein 4 (FBXL4).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of F-box/LRR-repeat protein 4 (FBXL4).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of F-box/LRR-repeat protein 4 (FBXL4).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of F-box/LRR-repeat protein 4 (FBXL4).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of F-box/LRR-repeat protein 4 (FBXL4).	[14]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of F-box/LRR-repeat protein 4 (FBXL4).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of F-box/LRR-repeat protein 4 (FBXL4).	[17]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of F-box/LRR-repeat protein 4 (FBXL4).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of F-box/LRR-repeat protein 4 (FBXL4).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of F-box/LRR-repeat protein 4 (FBXL4).	[14]

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 increases the methylation of F-box/LRR-repeat protein 4 (FBXL4).	[16]

References

• [1] FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome.Clin Genet. 2017 Apr;91(4):634-639. doi: 10.1111/cge.12894. Epub 2017 Jan 5.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Characterization of the C584R variant in the mtDNA depletion syndrome gene FBXL4, reveals a novel role for FBXL4 as a regulator of mitochondrial fusion.Biochim Biophys Acta Mol Basis Dis. 2019 Nov 1;1865(11):165536. doi: 10.1016/j.bbadis.2019.165536. Epub 2019 Aug 20.
• [4] Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder.Neuropsychopharmacology. 2018 Sep;43(10):2146-2153. doi: 10.1038/s41386-018-0078-9. Epub 2018 Apr 27.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.Am J Hum Genet. 2013 Sep 5;93(3):482-95. doi: 10.1016/j.ajhg.2013.07.016. Epub 2013 Aug 29.
• [7] Whole exome sequencing of suspected mitochondrial patients in clinical practice.J Inherit Metab Dis. 2015 May;38(3):437-43. doi: 10.1007/s10545-015-9823-y. Epub 2015 Mar 4.
• [8] Identification of FBXL4 as a Metastasis Associated Gene in Prostate Cancer.Sci Rep. 2017 Jul 11;7(1):5124. doi: 10.1038/s41598-017-05209-z.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [16] 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.
• [17] 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.
• [18] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.