Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOT7JCD)

• DOT Name: F-box and leucine-rich protein 22 (FBXL22)
• Gene Name: FBXL22
• Related Disease: Estrogen-receptor positive breast cancer
• UniProt ID: FXL22_HUMAN
• Pfam ID: PF12937
• Sequence:
  MWPLLTMHITQLNRECLLHLFSFLDKDSRKSLARTCSQLHDVFEDPALWSLLHFRSLTEL
  QKDNFLLGPALRSLSICWHSSRVQVCSIEDWLKSAFQRSICSRHESLVNDFLLRVCDRLS
  AVRSPRRREAPAPSSGTPIAVGPKSPRWGGPDHSEFADLRSGVTGARAAARRGLGSLRAE
  RPSETPPAPGVSWGPPPPGAPVVISVKQEEGKQGRTGRRSHRAAPPCGFARTRVCPPTFP
  GADAFPQ
• Function: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Promotes ubiquitination of sarcomeric proteins alpha-actinin-2 (ACTN2) and filamin-C (FLNC).
• Tissue Specificity: Enriched in cardiac muscle.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of F-box and leucine-rich protein 22 (FBXL22).	[2]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of F-box and leucine-rich protein 22 (FBXL22).	[3]
Marinol	DM70IK5	Approved	Marinol increases the expression of F-box and leucine-rich protein 22 (FBXL22).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of F-box and leucine-rich protein 22 (FBXL22).	[6]

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 decreases the methylation of F-box and leucine-rich protein 22 (FBXL22).	[5]

References

• [1] An exome-wide analysis of low frequency and rare variants in relation to risk of breast cancer in African American Women: the AMBER Consortium.Carcinogenesis. 2016 Sep;37(9):870-877. doi: 10.1093/carcin/bgw067. Epub 2016 Jun 7.
• [2] 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.
• [3] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [4] Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res. 2008 Jan 29;1191:1-11.
• [5] 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.
• [6] 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.