Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2A6RLR)

• DOT Name: F-box/WD repeat-containing protein 11 (FBXW11)
• Synonyms: F-box and WD repeats protein beta-TrCP2; F-box/WD repeat-containing protein 1B; Homologous to Slimb protein; HOS
• Gene Name: FBXW11
• Related Disease:
  Bladder cancer
  Epithelial neoplasm
  Atypical teratoid/rhabdoid tumour
  Autism, susceptibility to, 15
  Bone osteosarcoma
  Cervical cancer
  Cervical carcinoma
  Ewing sarcoma
  Eye disorder
  Familial adenomatous polyposis
  Hepatocellular carcinoma
  Holoprosencephaly
  Intellectual disability
  Lung adenocarcinoma
  Myeloid leukaemia
  Neoplasm
  Neuroblastoma
  Neurodevelopmental, jaw, eye, and digital syndrome
  Osteosarcoma
  Polydactyly
  Preaxial polydactyly of fingers
  Retinoblastoma
  Fibrosarcoma
  Prostate cancer
  Prostate carcinoma
  Small-cell lung cancer
  Syndromic intellectual disability
  Carcinoma of esophagus
  leukaemia
  Leukemia
  Lymphoid leukemia
  Advanced cancer
  Non-small-cell lung cancer
• UniProt ID: FBW1B_HUMAN
• PDB ID: 6WNX
• Pfam ID: PF12125 ; PF12937 ; PF00400
• Sequence:
  MEPDSVIEDKTIELMCSVPRSLWLGCANLVESMCALSCLQSMPSVRCLQISNGTSSVIVS
  RKRPSEGNYQKEKDLCIKYFDQWSESDQVEFVEHLISRMCHYQHGHINSYLKPMLQRDFI
  TALPEQGLDHIAENILSYLDARSLCAAELVCKEWQRVISEGMLWKKLIERMVRTDPLWKG
  LSERRGWDQYLFKNRPTDGPPNSFYRSLYPKIIQDIETIESNWRCGRHNLQRIQCRSENS
  KGVYCLQYDDEKIISGLRDNSIKIWDKTSLECLKVLTGHTGSVLCLQYDERVIVTGSSDS
  TVRVWDVNTGEVLNTLIHHNEAVLHLRFSNGLMVTCSKDRSIAVWDMASATDITLRRVLV
  GHRAAVNVVDFDDKYIVSASGDRTIKVWSTSTCEFVRTLNGHKRGIACLQYRDRLVVSGS
  SDNTIRLWDIECGACLRVLEGHEELVRCIRFDNKRIVSGAYDGKIKVWDLQAALDPRAPA
  STLCLRTLVEHSGRVFRLQFDEFQIISSSHDDTILIWDFLNVPPSAQNETRSPSRTYTYI
  SR
• Function: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Probably recognizes and binds to phosphorylated target proteins: the interaction with substrates requires the phosphorylation of the two serine residues in the substrates' destruction motif D-S-G-X(2,3,4)-S. SCF(FBXW11) mediates the ubiquitination of phosphorylated CTNNB1 and participates in Wnt signaling regulation. SCF(FBXW11) plays a key role in NF-kappa-B activation by mediating ubiquitination of phosphorylated NFKBIA, leading to its degradation by the proteasome, thereby allowing the associated NF-kappa-B complex to translocate into the nucleus and to activate transcription. The SCF(FBXW11) complex also regulates NF-kappa-B by mediating ubiquitination of phosphorylated NFKB1: specifically ubiquitinates the p105 form of NFKB1, leading to its degradation. SCF(FBXW11) mediates the ubiquitination of IFNAR1. SCF(FBXW11) mediates the ubiquitination of CEP68; this is required for centriole separation during mitosis. Involved in the oxidative stress-induced a ubiquitin-mediated decrease in RCAN1. Mediates the degradation of CDC25A induced by ionizing radiation in cells progressing through S phase and thus may function in the intra-S-phase checkpoint. Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and phosphorylated PER2. SCF(FBXW11) mediates the ubiquitination of CYTH1, and probably CYTH2. SCF(FBXW11) acts as a regulator of mTORC1 signaling pathway by catalyzing ubiquitination and subsequent proteasomal degradation of phosphorylated DEPTOR, TFE3 and MITF ; (Microbial infection) Target of human immunodeficiency virus type 1 (HIV-1) protein VPU to polyubiquitinate and deplete BST2 from cells and antagonize its antiviral action.
• KEGG Pathway:
  Oocyte meiosis (hsa04114)
  Ubiquitin mediated proteolysis (hsa04120)
  Cellular senescence (hsa04218)
  Wnt sig.ling pathway (hsa04310)
  Hedgehog sig.ling pathway (hsa04340)
  Hippo sig.ling pathway (hsa04390)
  Circadian rhythm (hsa04710)
  Shigellosis (hsa05131)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  Downstream TCR signaling (R-HSA-202424)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  NIK-->noncanonical NF-kB signaling (R-HSA-5676590)
  MAP3K8 (TPL2)-dependent MAPK1/3 activation (R-HSA-5684264)
  Neddylation (R-HSA-8951664)
  Antigen processing (R-HSA-983168)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Definitive	Biomarker	[1]
Epithelial neoplasm	DIS0T594	Definitive	Biomarker	[1]
Atypical teratoid/rhabdoid tumour	DIS1FA0D	Strong	Biomarker	[2]
Autism, susceptibility to, 15	DISYCG6A	Strong	Autosomal dominant	[3]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[6]
Eye disorder	DISB52BH	Strong	Biomarker	[3]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Holoprosencephaly	DISR35EC	Strong	Biomarker	[9]
Intellectual disability	DISMBNXP	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[10]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[13]
Neurodevelopmental, jaw, eye, and digital syndrome	DIS5569Z	Strong	Autosomal dominant	[3]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[4]
Polydactyly	DIS25BMZ	Strong	Biomarker	[9]
Preaxial polydactyly of fingers	DISXO6C9	Strong	Genetic Variation	[9]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[14]
Fibrosarcoma	DISWX7MU	moderate	Biomarker	[15]
Prostate cancer	DISF190Y	moderate	Biomarker	[16]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[16]
Small-cell lung cancer	DISK3LZD	moderate	Altered Expression	[17]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[3]
Carcinoma of esophagus	DISS6G4D	Disputed	Biomarker	[18]
leukaemia	DISS7D1V	Disputed	Biomarker	[19]
Leukemia	DISNAKFL	Disputed	Biomarker	[19]
Lymphoid leukemia	DIS65TYQ	Disputed	Altered Expression	[19]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[20]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Genetic Variation	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of F-box/WD repeat-containing protein 11 (FBXW11).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of F-box/WD repeat-containing protein 11 (FBXW11).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of F-box/WD repeat-containing protein 11 (FBXW11).	[25]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of F-box/WD repeat-containing protein 11 (FBXW11).	[28]

3 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 affects the methylation of F-box/WD repeat-containing protein 11 (FBXW11).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of F-box/WD repeat-containing protein 11 (FBXW11).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of F-box/WD repeat-containing protein 11 (FBXW11).	[27]

References

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• [4] Inhibitory Effects of Indomethacin in Human MNNG/HOS Osteosarcoma Cell Line InVitro.Cancer Invest. 2020 Jan;38(1):23-36. doi: 10.1080/07357907.2019.1698592. Epub 2019 Dec 16.
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• [9] Holoprosencephaly and preaxial polydactyly associated with a 1.24 Mb duplication encompassing FBXW11 at 5q35.1.J Hum Genet. 2006;51(8):721-726. doi: 10.1007/s10038-006-0010-8. Epub 2006 Jul 25.
• [10] Multiplex Diagnosis of Oncogenic Fusion and MET Exon Skipping by Molecular Counting Using Formalin-Fixed Paraffin Embedded Lung Adenocarcinoma Tissues.J Thorac Oncol. 2016 Feb;11(2):203-12. doi: 10.1016/j.jtho.2015.10.005. Epub 2015 Dec 19.
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• [18] Overexpression of GML promotes radiation-induced cell cycle arrest and apoptosis.Biochem Biophys Res Commun. 1997 Dec 18;241(2):481-5. doi: 10.1006/bbrc.1997.7818.
• [19] Fbxw11 promotes the proliferation of lymphocytic leukemia cells through the concomitant activation of NF-B and -catenin/TCF signaling pathways.Cell Death Dis. 2018 Apr 1;9(4):427. doi: 10.1038/s41419-018-0440-1.
• [20] Tip60-dependent acetylation of KDM2B promotes osteosarcoma carcinogenesis.J Cell Mol Med. 2019 Sep;23(9):6154-6163. doi: 10.1111/jcmm.14497. Epub 2019 Jun 20.
• [21] Optimization of Routine Testing for MET Exon 14 Splice Site Mutations in NSCLC Patients.J Thorac Oncol. 2018 Dec;13(12):1873-1883. doi: 10.1016/j.jtho.2018.08.2023. Epub 2018 Sep 7.
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• [24] 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.
• [25] 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.
• [26] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [27] 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.
• [28] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.