Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW4455M)

• DOT Name: F-box/LRR-repeat protein 18 (FBXL18)
• Synonyms: F-box and leucine-rich repeat protein 18
• Gene Name: FBXL18
• Related Disease:
  Hepatocellular carcinoma
  Glioma
• UniProt ID: FXL18_HUMAN
• Pfam ID: PF12937 ; PF19729
• Sequence:
  MASSGEDISNDDDDMHPAAAGMADGVHLLGFSDEILLHILSHVPSTDLILNVRRTCRKLA
  ALCLDKSLIHTVLLQKDYQASEDKVRQLVKEIGREIQQLSMAGCYWLPGSTVEHVARCRS
  LVKVNLSGCHLTSLRLSKMLSALQHLRSLAIDVSPGFDASQLSSECKATLSRVRELKQTL
  FTPSYGVVPCCTSLEKLLLYFEILDRTREGAILSGQLMVGQSNVPHYQNLRVFYARLAPG
  YINQEVVRLYLAVLSDRTPQNLHAFLISVPGSFAESGATKNLLDSMARNVVLDALQLPKS
  WLNGSSLLQHMKFNNPFYFSFSRCTLSGGHLIQQVINGGKDLRSLASLNLSGCVHCLSPD
  SLLRKAEDDIDSSILETLVASCCNLRHLNLSAAHHHSSEGLGRHLCQLLARLRHLRSLSL
  PVCSVADSAPRADRAPAQPAMHAVPRGFGKKVRVGVQSCPSPFSGQACPQPSSVFWSLLK
  NLPFLEHLELIGSNFSSAMPRNEPAIRNSLPPCSRAQSVGDSEVAAIGQLAFLRHLTLAQ
  LPSVLTGSGLVNIGLQCQQLRSLSLANLGMMGKVVYMPALSDMLKHCKRLRDLRLEQPYF
  SANAQFFQALSQCPSLQRLCLVSRSGTLQPDAVLAFMARCLQVVMCHLFTGESLATCKSL
  QQSLLRSFQAERPALNVVIFPLLHEGLTDVIRDVPLVHLDEITLFKSRVAEEPPNLWW
• Function: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  Antigen processing (R-HSA-983168)
  FBXL7 down-regulates AURKA during mitotic entry and in early mitosis (R-HSA-8854050)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of F-box/LRR-repeat protein 18 (FBXL18).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of F-box/LRR-repeat protein 18 (FBXL18).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of F-box/LRR-repeat protein 18 (FBXL18).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of F-box/LRR-repeat protein 18 (FBXL18).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of F-box/LRR-repeat protein 18 (FBXL18).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of F-box/LRR-repeat protein 18 (FBXL18).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of F-box/LRR-repeat protein 18 (FBXL18).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of F-box/LRR-repeat protein 18 (FBXL18).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of F-box/LRR-repeat protein 18 (FBXL18).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of F-box/LRR-repeat protein 18 (FBXL18).	[12]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] The F-box protein FBXL18 promotes glioma progression by promoting K63-linked ubiquitination of Akt.FEBS Lett. 2017 Jan;591(1):145-154. doi: 10.1002/1873-3468.12521. Epub 2016 Dec 20.
• [3] 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.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.