Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXQ51E0)

• DOT Name: F-box-like/WD repeat-containing protein TBL1X (TBL1X)
• Synonyms: SMAP55; Transducin beta-like protein 1X; Transducin-beta-like protein 1, X-linked
• Gene Name: TBL1X
• Related Disease: Hypothyroidism, congenital, nongoitrous, 8
• UniProt ID: TBL1X_HUMAN
• PDB ID: 2XTC; 2XTD; 2XTE
• Pfam ID: PF08513 ; PF00400
• Sequence:
  MTELAGASSSCCHRPAGRGAMQSVLHHFQRLRGREGGSHFINTSSPRGEAKMSITSDEVN
  FLVYRYLQESGFSHSAFTFGIESHISQSNINGTLVPPAALISILQKGLQYVEAEISINED
  GTVFDGRPIESLSLIDAVMPDVVQTRQQAFREKLAQQQASAAAAAAAATAAATAATTTSA
  GVSHQNPSKNREATVNGEENRAHSVNNHAKPMEIDGEVEIPSSKATVLRGHESEVFICAW
  NPVSDLLASGSGDSTARIWNLNENSNGGSTQLVLRHCIREGGHDVPSNKDVTSLDWNTNG
  TLLATGSYDGFARIWTEDGNLASTLGQHKGPIFALKWNRKGNYILSAGVDKTTIIWDAHT
  GEAKQQFPFHSAPALDVDWQNNTTFASCSTDMCIHVCRLGCDRPVKTFQGHTNEVNAIKW
  DPSGMLLASCSDDMTLKIWSMKQEVCIHDLQAHNKEIYTIKWSPTGPATSNPNSNIMLAS
  ASFDSTVRLWDIERGVCTHTLTKHQEPVYSVAFSPDGKYLASGSFDKCVHIWNTQSGNLV
  HSYRGTGGIFEVCWNARGDKVGASASDGSVCVLDLRK
• Function: F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units. Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of corepressor complexes that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of transcription repressor complexes, thereby allowing cofactor exchange.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway:
  BMAL1 (R-HSA-1368108)
  PPARA activates gene expression (R-HSA-1989781)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  HDACs deacetylate histones (R-HSA-3214815)
  Notch-HLH transcription pathway (R-HSA-350054)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  Regulation of lipid metabolism by PPARalpha (R-HSA-400206)
  Circadian Clock (R-HSA-400253)
  Loss of MECP2 binding ability to the NCoR/SMRT complex (R-HSA-9022537)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  HCMV Early Events (R-HSA-9609690)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  Heme signaling (R-HSA-9707616)
  RORA activates gene expression (R-HSA-1368082)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypothyroidism, congenital, nongoitrous, 8	DISYPNF7	Limited	Unknown	[1]

3 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-like/WD repeat-containing protein TBL1X (TBL1X).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[12]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[14]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[15]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[18]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[22]
AM251	DMTAWHL	Investigative	AM251 increases the expression of F-box-like/WD repeat-containing protein TBL1X (TBL1X).	[23]

References

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• [2] 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.
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• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] 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.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] 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.
• [12] 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.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [15] 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.
• [16] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.