Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDQ1QKV)

• DOT Name: F-box/LRR-repeat protein 3 (FBXL3)
• Synonyms: F-box and leucine-rich repeat protein 3A; F-box/LRR-repeat protein 3A
• Gene Name: FBXL3
• Related Disease:
  Bipolar disorder
  Colorectal carcinoma
  Intellectual disability
  Neoplasm
  Non-small-cell lung cancer
  Advanced cancer
  Intellectual disability, short stature, facial anomalies, and joint dislocations
  Neuronal ceroid lipofuscinosis
  Neuronal ceroid lipofuscinosis 5
• UniProt ID: FBXL3_HUMAN
• PDB ID: 4I6J
• Pfam ID: PF12937
• Sequence:
  MKRGGRDSDRNSSEEGTAEKSKKLRTTNEHSQTCDWGNLLQDIILQVFKYLPLLDRAHAS
  QVCRNWNQVFHMPDLWRCFEFELNQPATSYLKATHPELIKQIIKRHSNHLQYVSFKVDSS
  KESAEAACDILSQLVNCSLKTLGLISTARPSFMDLPKSHFISALTVVFVNSKSLSSLKID
  DTPVDDPSLKVLVANNSDTLKLLKMSSCPHVSPAGILCVADQCHGLRELALNYHLLSDEL
  LLALSSEKHVRLEHLRIDVVSENPGQTHFHTIQKSSWDAFIRHSPKVNLVMYFFLYEEEF
  DPFFRYEIPATHLYFGRSVSKDVLGRVGMTCPRLVELVVCANGLRPLDEELIRIAERCKN
  LSAIGLGECEVSCSAFVEFVKMCGGRLSQLSIMEEVLIPDQKYSLEQIHWEVSKHLGRVW
  FPDMMPTW
• Function: Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex involved in circadian rhythm function. Plays a key role in the maintenance of both the speed and the robustness of the circadian clock oscillation. The SCF(FBXL3) complex mainly acts in the nucleus and mediates ubiquitination and subsequent degradation of CRY1 and CRY2. Activity of the SCF(FBXL3) complex is counteracted by the SCF(FBXL21) complex.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Circadian rhythm (hsa04710)
• Reactome Pathway:
  Circadian Clock (R-HSA-400253)
  Neddylation (R-HSA-8951664)
  Antigen processing (R-HSA-983168)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[5]
Intellectual disability, short stature, facial anomalies, and joint dislocations	DISXP6H7	Limited	Autosomal recessive	[6]
Neuronal ceroid lipofuscinosis	DIS9A4K4	Limited	CausalMutation	[7]
Neuronal ceroid lipofuscinosis 5	DISSKW1M	Limited	Genetic Variation	[7]

7 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/LRR-repeat protein 3 (FBXL3).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of F-box/LRR-repeat protein 3 (FBXL3).	[9]
Aspirin	DM672AH	Approved	Aspirin increases the expression of F-box/LRR-repeat protein 3 (FBXL3).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of F-box/LRR-repeat protein 3 (FBXL3).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of F-box/LRR-repeat protein 3 (FBXL3).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of F-box/LRR-repeat protein 3 (FBXL3).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of F-box/LRR-repeat protein 3 (FBXL3).	[14]

References

• [1] Reduced anxiety and depression-like behaviours in the circadian period mutant mouse afterhours.PLoS One. 2012;7(6):e38263. doi: 10.1371/journal.pone.0038263. Epub 2012 Jun 15.
• [2] miR-181d and c-myc-mediated inhibition of CRY2 and FBXL3 reprograms metabolism in colorectal cancer.Cell Death Dis. 2017 Jul 27;8(7):e2958. doi: 10.1038/cddis.2017.300.
• [3] Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature.Hum Mol Genet. 2019 Mar 15;28(6):972-979. doi: 10.1093/hmg/ddy406.
• [4] FBXL3 is regulated by miRNA-4735-3p and suppresses cell proliferation and migration in non-small cell lung cancer.Pathol Res Pract. 2019 Feb;215(2):358-365. doi: 10.1016/j.prp.2018.12.008. Epub 2018 Dec 11.
• [5] CRY2 and FBXL3 Cooperatively Degrade c-MYC.Mol Cell. 2016 Nov 17;64(4):774-789. doi: 10.1016/j.molcel.2016.10.012. Epub 2016 Nov 10.
• [6] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [7] Proteolytic processing of the neuronal ceroid lipofuscinosis related lysosomal protein CLN5.Exp Cell Res. 2015 Oct 15;338(1):45-53. doi: 10.1016/j.yexcr.2015.08.021. Epub 2015 Sep 3.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [10] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] 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.
• [14] 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.