Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD4D2OP)

• DOT Name: F-box/SPRY domain-containing protein 1 (FBXO45)
• Synonyms: F-box only protein 45; hFbxo45
• Gene Name: FBXO45
• Related Disease:
  Gastric cancer
  Stomach cancer
  Advanced cancer
  Colorectal carcinoma
  Lung squamous cell carcinoma
  Neoplasm
  Neuralgia
  Schizophrenia
• UniProt ID: FBSP1_HUMAN
• Pfam ID: PF12937 ; PF00622
• Sequence:
  MAAPAPGAGAASGGAGCSGGGAGAGAGSGSGAAGAGGRLPSRVLELVFSYLELSELRSCA
  LVCKHWYRCLHGDENSEVWRSLCARSLAEEALRTDILCNLPSYKAKIRAFQHAFSTNDCS
  RNVYIKKNGFTLHRNPIAQSTDGARTKIGFSEGRHAWEVWWEGPLGTVAVIGIATKRAPM
  QCQGYVALLGSDDQSWGWNLVDNNLLHNGEVNGSFPQCNNAPKYQIGERIRVILDMEDKT
  LAFERGYEFLGVAFRGLPKVCLYPAVSAVYGNTEVTLVYLGKPLDG
• Function: Component of E3 ubiquitin ligase complex consisting of FBXO45, MYCBP2 and SKP1. Functions in substrate recognition but plays also an important role in assembly of the complex. Required for normal neuromuscular synaptogenesis, axon pathfinding and neuronal migration. Regulates neuron migration during brain development through interaction with N-cadherin/CDH2 after secretion via a non-classical mechanism. Plays a role in the regulation of neurotransmission at mature neurons. May control synaptic activity by controlling UNC13A via ubiquitin dependent pathway. Specifically recognizes TP73, promoting its ubiquitination and degradation. Polyubiquitinates NMNAT2, an adenylyltransferase that acts as an axon maintenance factor, and regulates its stability and degradation by the proteasome. Acts also by ubiquitinating FBXW7 during prolonged mitotic arrest and promotes FBXW7 proteasomal degradation. Induces subsequently an increase in mitotic slippage and prevents mitotic cell death. In response to influenza infection, mediates interferon-lambda receptor IFNLR1 polyubiquitination and degradation through the ubiquitin-proteasome system by docking with its intracellular receptor domain.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Definitive	Biomarker	[1]
Stomach cancer	DISKIJSX	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Neuralgia	DISWO58J	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[6]

7 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/SPRY domain-containing protein 1 (FBXO45).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of F-box/SPRY domain-containing protein 1 (FBXO45).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of F-box/SPRY domain-containing protein 1 (FBXO45).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of F-box/SPRY domain-containing protein 1 (FBXO45).	[11]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of F-box/SPRY domain-containing protein 1 (FBXO45).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of F-box/SPRY domain-containing protein 1 (FBXO45).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of F-box/SPRY domain-containing protein 1 (FBXO45).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of F-box/SPRY domain-containing protein 1 (FBXO45).	[10]

References

• [1] Low Expression of FBXO45 Is Associated with Gastric Cancer Progression and Poor Prognosis.Anticancer Res. 2017 Jan;37(1):191-196. doi: 10.21873/anticanres.11305.
• [2] m(6)A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1.Mol Cancer. 2019 Apr 13;18(1):87. doi: 10.1186/s12943-019-1014-2.
• [3] Identification of aberrantly expressed F-box proteins in squamous-cell lung carcinoma.J Cancer Res Clin Oncol. 2018 Aug;144(8):1509-1521. doi: 10.1007/s00432-018-2653-1. Epub 2018 May 4.
• [4] Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival.Cell Death Differ. 2014 Oct;21(10):1535-45. doi: 10.1038/cdd.2014.92. Epub 2014 Jul 4.
• [5] Spinal TNF- impedes Fbxo45-dependent Munc13-1 ubiquitination to mediate neuropathic allodynia in rats.Cell Death Dis. 2018 Jul 24;9(8):811. doi: 10.1038/s41419-018-0859-4.
• [6] Novel rare variants in F-box protein 45 (FBXO45) in schizophrenia.Schizophr Res. 2014 Aug;157(1-3):149-56. doi: 10.1016/j.schres.2014.04.032. Epub 2014 May 28.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [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] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [11] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [12] 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.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.