Details of Drug Off-Target (DOT)

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

• DOT Name: Histone deacetylase 1 (HDAC1)
• Synonyms: HD1; EC 3.5.1.98; Protein deacetylase HDAC1; EC 3.5.1.-; Protein decrotonylase HDAC1; EC 3.5.1.-
• Gene Name: HDAC1
• Related Disease: Congenital heart disease
• UniProt ID: HDAC1_HUMAN
• PDB ID: 4BKX; 5ICN; 6Z2J; 6Z2K; 7AO8; 7AO9; 7AOA; 7SME
• EC Number: 3.5.1.-; 3.5.1.98
• Pfam ID: PF00850
• Sequence:
  MAQTQGTRRKVCYYYDGDVGNYYYGQGHPMKPHRIRMTHNLLLNYGLYRKMEIYRPHKAN
  AEEMTKYHSDDYIKFLRSIRPDNMSEYSKQMQRFNVGEDCPVFDGLFEFCQLSTGGSVAS
  AVKLNKQQTDIAVNWAGGLHHAKKSEASGFCYVNDIVLAILELLKYHQRVLYIDIDIHHG
  DGVEEAFYTTDRVMTVSFHKYGEYFPGTGDLRDIGAGKGKYYAVNYPLRDGIDDESYEAI
  FKPVMSKVMEMFQPSAVVLQCGSDSLSGDRLGCFNLTIKGHAKCVEFVKSFNLPMLMLGG
  GGYTIRNVARCWTYETAVALDTEIPNELPYNDYFEYFGPDFKLHISPSNMTNQNTNEYLE
  KIKQRLFENLRMLPHAPGVQMQAIPEDAIPEESGDEDEDDPDKRISICSSDKRIACEEEF
  SDSEEEGEGGRKNSSNFKKAKRVKTEDEKEKDPEEKKEVTEEEKTKEEKPEAKGVKEEVK
  LA
• Function: Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin. As part of the SIN3B complex is recruited downstream of the constitutively active genes transcriptional start sites through interaction with histones and mitigates histone acetylation and RNA polymerase II progression within transcribed regions contributing to the regulation of transcription. Also functions as a deacetylase for non-histone targets, such as NR1D2, RELA, SP1, SP3, STAT3 and TSHZ3. Deacetylates SP proteins, SP1 and SP3, and regulates their function. Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons. Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B. Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-BMAL1 heterodimer. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation. In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones.
• Tissue Specificity: Ubiquitous, with higher levels in heart, pancreas and testis, and lower levels in kidney and brain.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Polycomb repressive complex (hsa03083)
  Cell cycle (hsa04110)
  Longevity regulating pathway - multiple species (hsa04213)
  Notch sig.ling pathway (hsa04330)
  TGF-beta sig.ling pathway (hsa04350)
  Neutrophil extracellular trap formation (hsa04613)
  Thyroid hormone sig.ling pathway (hsa04919)
  Huntington disease (hsa05016)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
  Human papillomavirus infection (hsa05165)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Viral carcinogenesis (hsa05203)
  MicroR.s in cancer (hsa05206)
  Chronic myeloid leukemia (hsa05220)
• Reactome Pathway:
  Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 (R-HSA-1362300)
  G0 and Early G1 (R-HSA-1538133)
  p75NTR negatively regulates cell cycle via SC1 (R-HSA-193670)
  Formation of the beta-catenin (R-HSA-201722)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Downregulation of SMAD2/3 (R-HSA-2173795)
  SMAD2/SMAD3 (R-HSA-2173796)
  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)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (R-HSA-427389)
  NoRC negatively regulates rRNA expression (R-HSA-427413)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  Repression of WNT target genes (R-HSA-4641265)
  Regulation of TP53 Activity through Acetylation (R-HSA-6804758)
  G1/S-Specific Transcription (R-HSA-69205)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Loss of MECP2 binding ability to 5mC-DNA (R-HSA-9022538)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  MECP2 regulates neuronal receptors and channels (R-HSA-9022699)
  MECP2 regulates transcription of neuronal ligands (R-HSA-9022702)
  FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017)
  Potential therapeutics for SARS (R-HSA-9679191)
  STAT3 nuclear events downstream of ALK signaling (R-HSA-9701898)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Transcription of E2F targets under negative control by DREAM complex (R-HSA-1362277)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital heart disease	DISQBA23	Disputed	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Histone deacetylase 1 (HDAC1).	[2]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Histone deacetylase 1 (HDAC1).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Histone deacetylase 1 (HDAC1).	[30]

33 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 Histone deacetylase 1 (HDAC1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Histone deacetylase 1 (HDAC1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Histone deacetylase 1 (HDAC1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone deacetylase 1 (HDAC1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Histone deacetylase 1 (HDAC1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Histone deacetylase 1 (HDAC1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Histone deacetylase 1 (HDAC1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Histone deacetylase 1 (HDAC1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Histone deacetylase 1 (HDAC1).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Histone deacetylase 1 (HDAC1).	[12]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Histone deacetylase 1 (HDAC1).	[13]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Histone deacetylase 1 (HDAC1).	[14]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Histone deacetylase 1 (HDAC1).	[15]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Histone deacetylase 1 (HDAC1).	[16]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of Histone deacetylase 1 (HDAC1).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Histone deacetylase 1 (HDAC1).	[18]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Histone deacetylase 1 (HDAC1).	[19]
HMPL-004	DM29XGY	Phase 3	HMPL-004 decreases the expression of Histone deacetylase 1 (HDAC1).	[20]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Histone deacetylase 1 (HDAC1).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Histone deacetylase 1 (HDAC1).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Histone deacetylase 1 (HDAC1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histone deacetylase 1 (HDAC1).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Histone deacetylase 1 (HDAC1).	[26]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the activity of Histone deacetylase 1 (HDAC1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Histone deacetylase 1 (HDAC1).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the activity of Histone deacetylase 1 (HDAC1).	[29]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Histone deacetylase 1 (HDAC1).	[31]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Histone deacetylase 1 (HDAC1).	[32]
15-deoxy-Delta(12, 14)-prostaglandin J(2)	DM8VUX3	Investigative	15-deoxy-Delta(12, 14)-prostaglandin J(2) decreases the expression of Histone deacetylase 1 (HDAC1).	[33]
OLEANOLIC_ACID	DMWDMJ3	Investigative	OLEANOLIC_ACID decreases the expression of Histone deacetylase 1 (HDAC1).	[34]
BAY11-7082	DMQNOFA	Investigative	BAY11-7082 increases the expression of Histone deacetylase 1 (HDAC1).	[33]
MANGOSTIN	DMYQGDV	Investigative	MANGOSTIN increases the expression of Histone deacetylase 1 (HDAC1).	[35]
Oxalic Acid	DMLN2GQ	Investigative	Oxalic Acid increases the expression of Histone deacetylase 1 (HDAC1).	[36]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
GSK618334	DMJPXZ4	Phase 1	GSK618334 affects the binding of Histone deacetylase 1 (HDAC1).	[25]

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