Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBTN6WS)

• DOT Name: F-box/LRR-repeat protein 14 (FBXL14)
• Synonyms: F-box and leucine-rich repeat protein 14
• Gene Name: FBXL14
• Related Disease:
  Breast cancer
  Breast carcinoma
  Pancreatic cancer
  Neoplasm
  Nervous system disease
• UniProt ID: FXL14_HUMAN
• Pfam ID: PF12937 ; PF13516
• Sequence:
  METHISCLFPELLAMIFGYLDVRDKGRAAQVCTAWRDAAYHKSVWRGVEAKLHLRRANPS
  LFPSLQARGIRRVQILSLRRSLSYVIQGMANIESLNLSGCYNLTDNGLGHAFVQEIGSLR
  ALNLSLCKQITDSSLGRIAQYLKGLEVLELGGCSNITNTGLLLIAWGLQRLKSLNLRSCR
  HLSDVGIGHLAGMTRSAAEGCLGLEQLTLQDCQKLTDLSLKHISRGLTGLRLLNLSFCGG
  ISDAGLLHLSHMGSLRSLNLRSCDNISDTGIMHLAMGSLRLSGLDVSFCDKVGDQSLAYI
  AQGLDGLKSLSLCSCHISDDGINRMVRQMHGLRTLNIGQCVRITDKGLELIAEHLSQLTG
  IDLYGCTRITKRGLERITQLPCLKVLNLGLWQMTDSEKEARGDFSPLFTVRTRGSSRR
• Function: Substrate-recognition component of some SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin-protein ligase complexes. The SCF(FBXL14) complex acts by mediating ubiquitination and subsequent degradation of SNAI1.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Pancreatic cancer	DISJC981	moderate	Biomarker	[2]
Neoplasm	DISZKGEW	Limited	Biomarker	[3]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[4]

2 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/LRR-repeat protein 14 (FBXL14).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of F-box/LRR-repeat protein 14 (FBXL14).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of F-box/LRR-repeat protein 14 (FBXL14).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of F-box/LRR-repeat protein 14 (FBXL14).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of F-box/LRR-repeat protein 14 (FBXL14).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of F-box/LRR-repeat protein 14 (FBXL14).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of F-box/LRR-repeat protein 14 (FBXL14).	[11]

References

• [1] FBXL14 abolishes breast cancer progression by targeting CDCP1 for proteasomal degradation.Oncogene. 2018 Oct;37(43):5794-5809. doi: 10.1038/s41388-018-0372-3. Epub 2018 Jul 4.
• [2] LKB1 obliterates Snail stability and inhibits pancreatic cancer metastasis in response to metformin treatment.Cancer Sci. 2018 May;109(5):1382-1392. doi: 10.1111/cas.13591.
• [3] Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination.J Exp Med. 2017 Jan;214(1):245-267. doi: 10.1084/jem.20151673. Epub 2016 Dec 6.
• [4] 1.39 Mb inherited interstitial deletion in 12p13.33 associated with developmental delay.Eur J Med Genet. 2011 Mar-Apr;54(2):198-203. doi: 10.1016/j.ejmg.2010.11.010. Epub 2010 Dec 7.
• [5] 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.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] 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.
• [10] 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.
• [11] 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.