Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGWF3Q2)

• DOT Name: F-box only protein 11 (FBXO11)
• Synonyms: Protein arginine N-methyltransferase 9; Vitiligo-associated protein 1; VIT-1
• Gene Name: FBXO11
• Related Disease: Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities
• UniProt ID: FBX11_HUMAN
• PDB ID: 5VMD
• Pfam ID: PF13229 ; PF12937 ; PF02207
• Sequence:
  MNSVRAANRRPRRVSRPRPVQQQQQQPPQQPPPQPPQQQPPQQQPPPPPQQQQQQQPPPP
  PPPPPPLPQERNNVGERDDDVPADMVAEESGPGAQNSPYQLRRKTLLPKRTACPTKNSME
  GASTSTTENFGHRAKRARVSGKSQDLSAAPAEQYLQEKLPDEVVLKIFSYLLEQDLCRAA
  CVCKRFSELANDPILWKRLYMEVFEYTRPMMHPEPGKFYQINPEEYEHPNPWKESFQQLY
  KGAHVKPGFAEHFYSNPARYKGRENMLYYDTIEDALGGVQEAHFDGLIFVHSGIYTDEWI
  YIESPITMIGAAPGKVADKVIIENTRDSTFVFMEGSEDAYVGYMTIRFNPDDKSAQHHNA
  HHCLEITVNCSPIIDHCIIRSTCTVGSAVCVSGQGACPTIKHCNISDCENVGLYITDHAQ
  GIYEDNEISNNALAGIWVKNHGNPIIRRNHIHHGRDVGVFTFDHGMGYFESCNIHRNRIA
  GFEVKAYANPTVVRCEIHHGQTGGIYVHEKGRGQFIENKIYANNFAGVWITSNSDPTIRG
  NSIFNGNQGGVYIFGDGRGLIEGNDIYGNALAGIQIRTNSCPIVRHNKIHDGQHGGIYVH
  EKGQGVIEENEVYSNTLAGVWVTTGSTPVLRRNRIHSGKQVGVYFYDNGHGVLEDNDIYN
  HMYSGVQIRTGSNPKIRRNKIWGGQNGGILVYNSGLGCIEDNEIFDNAMAGVWIKTDSNP
  TLRRNKIHDGRDGGICIFNGGRGLLEENDIFRNAQAGVLISTNSHPILRKNRIFDGFAAG
  IEITNHATATLEGNQIFNNRFGGLFLASGVNVTMKDNKIMNNQDAIEKAVSRGQCLYKIS
  SYTSYPMHDFYRCHTCNTTDRNAICVNCIKKCHQGHDVEFIRHDRFFCDCGAGTLSNPCT
  LAGEPTHDTDTLYDSAPPIESNTLQHN
• 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, such as DTL/CDT2, BCL6 and PRDM1/BLIMP1. The SCF(FBXO11) complex mediates ubiquitination and degradation of BCL6, thereby playing a role in the germinal center B-cells terminal differentiation toward memory B-cells and plasma cells. The SCF(FBXO11) complex also mediates ubiquitination and degradation of DTL, an important step for the regulation of TGF-beta signaling, cell migration and the timing of the cell-cycle progression and exit. Binds to and neddylates phosphorylated p53/TP53, inhibiting its transcriptional activity. Plays a role in the regulatiom of erythropoiesis but not myelopoiesis or megakaryopoiesis. Mechanistically, activates erythroid genes by mediating the degradation of BAHD1, a heterochromatin-associated protein that recruits corepressors to H3K27me3 marks. Participates in macrophage cell death and inflammation in response to bacterial toxins by regulating the expression of complement 5a receptor 1/C5AR1 and IL-1beta. Acts as a critical regulator to determine the level of MHC-II by mediating the recognition of degron at the P/S/T domain of CIITA leading to its ubiquitination and subsequent degradation via the proteasome. Participates in the antiviral repsonse by initiating the activation of TBK1-IRF3-IFN-I axis. Mediates the 'Lys-63'-linked ubiquitination of TRAF3 to strengthen the interaction between TRAF3 and TBK1.
• Tissue Specificity: Isoform 5 is expressed in keratinocytes, fibroblasts and melanocytes.
• 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
Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities	DISJZ467	Definitive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	F-box only protein 11 (FBXO11) affects the response to substance of Josamycin.	[15]

12 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 only protein 11 (FBXO11).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of F-box only protein 11 (FBXO11).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of F-box only protein 11 (FBXO11).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of F-box only protein 11 (FBXO11).	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of F-box only protein 11 (FBXO11).	[6]
Selenium	DM25CGV	Approved	Selenium decreases the expression of F-box only protein 11 (FBXO11).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of F-box only protein 11 (FBXO11).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of F-box only protein 11 (FBXO11).	[9]
Aspirin	DM672AH	Approved	Aspirin increases the expression of F-box only protein 11 (FBXO11).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of F-box only protein 11 (FBXO11).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of F-box only protein 11 (FBXO11).	[13]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of F-box only protein 11 (FBXO11).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of F-box only protein 11 (FBXO11).	[12]

References

• [1] 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.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [7] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [8] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [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] 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.
• [12] 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.
• [13] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [14] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.
• [15] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.