Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM3B3OA)

• DOT Name: F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1)
• Synonyms: Nuclear receptor corepressor/HDAC3 complex subunit TBLR1; TBL1-related protein 1; Transducin beta-like 1X-related protein 1
• Gene Name: TBL1XR1
• Related Disease:
  Complex neurodevelopmental disorder
  Pierpont syndrome
  Intellectual disability, autosomal dominant 41
• UniProt ID: TBL1R_HUMAN
• PDB ID: 4LG9
• Pfam ID: PF08513 ; PF00400
• Sequence:
  MSISSDEVNFLVYRYLQESGFSHSAFTFGIESHISQSNINGALVPPAALISIIQKGLQYV
  EAEVSINEDGTLFDGRPIESLSLIDAVMPDVVQTRQQAYRDKLAQQQAAAAAAAAAAASQ
  QGSAKNGENTANGEENGAHTIANNHTDMMEVDGDVEIPPNKAVVLRGHESEVFICAWNPV
  SDLLASGSGDSTARIWNLSENSTSGSTQLVLRHCIREGGQDVPSNKDVTSLDWNSEGTLL
  ATGSYDGFARIWTKDGNLASTLGQHKGPIFALKWNKKGNFILSAGVDKTTIIWDAHTGEA
  KQQFPFHSAPALDVDWQSNNTFASCSTDMCIHVCKLGQDRPIKTFQGHTNEVNAIKWDPT
  GNLLASCSDDMTLKIWSMKQDNCVHDLQAHNKEIYTIKWSPTGPGTNNPNANLMLASASF
  DSTVRLWDVDRGICIHTLTKHQEPVYSVAFSPDGRYLASGSFDKCVHIWNTQTGALVHSY
  RGTGGIFEVCWNAAGDKVGASASDGSVCVLDLRK
• 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 the N-Cor corepressor complex that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of N-Cor complex, thereby allowing cofactor exchange, and transcription activation.
• Tissue Specificity: Widely expressed including the pituitary, hypothalamus, white and brown adipose tissue, muscle and liver.
• 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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Pierpont syndrome	DISD1WJ1	Definitive	Autosomal dominant	[2]
Intellectual disability, autosomal dominant 41	DISW6ZUD	Strong	Autosomal dominant	[3]

21 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-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat affects the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[15]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[17]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[21]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[25]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[26]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of F-box-like/WD repeat-containing protein TBL1XR1 (TBL1XR1).	[19]

References

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