Molecule Information

General Information of the Molecule (ID: Mol04402)

• Name: Histone deacetylase 1 (HDAC1) ,Homo sapiens
• Synonyms: Protein deacetylase HDAC1; Protein deacylase HDAC1
• Molecule Type: Protein
• Gene Name: HDAC1
• Gene ID: 3065
• Sequence:
  MAQTQGTRRKVCYYYDGDVGNYYYGQGHPMKPHRIRMTHNLLLNYGLYRKMEIYRPHKAN
  AEEMTKYHSDDYIKFLRSIRPDNMSEYSKQMQRFNVGEDCPVFDGLFEFCQLSTGGSVA
  S AVKLNKQQTDIAVNWAGGLHHAKKSEASGFCYVNDIVLAILELLKYHQRVLYIDIDIH
  HG DGVEEAFYTTDRVMTVSFHKYGEYFPGTGDLRDIGAGKGKYYAVNYPLRDGIDDESY
  EAI FKPVMSKVMEMFQPSAVVLQCGSDSLSGDRLGCFNLTIKGHAKCVEFVKSFNLPML
  MLGG GGYTIRNVARCWTYETAVALDTEIPNELPYNDYFEYFGPDFKLHISPSNMTNQNT
  NEYLE KIKQRLFENLRMLPHAPGVQMQAIPEDAIPEESGDEDEDDPDKRISICSSDKRI
  ACEEEF SDSEEEGEGGRKNSSNFKKAKRVKTEDEKEKDPEEKKEVTEEEKTKEEKPEAK
  GVKEEVK LA
• Function: Histone deacetylase that catalyzes the deacetylation oflysine residues on the N-terminal part of the core histones . Histonedeacetylation gives a tag for epigenetic repression and plays animportant role in transcriptional regulation, cell cycle progressionand developmental events . Histonedeacetylases act via the formation of large multiprotein complexes. Acts as a component of the histonedeacetylase NuRD complex which participates in the remodeling ofchromatin . As part of the SIN3Bcomplex is recruited downstream of the constitutively active genestranscriptional start sites through interaction with histones andmitigates histone acetylation and RNA polymerase II progression withintranscribed regions contributing to the regulation of transcription. Also functions as a deacetylase for non-histonetargets, such as NR1D2, RELA, SP1, SP3, STAT3 and TSHZ3. Deacetylates SP proteins, SP1 and SP3, and regulatestheir function . Component of theBRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediatedtranscription in resting neurons . Upon calciumstimulation, HDAC1 is released from the complex and CREBBP isrecruited, which facilitates transcriptional activation. Deacetylates TSHZ3 and regulates its transcriptionalrepressor activity . Deacetylates 'Lys-310' in RELAand 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 thatsuppresses, via histone deacetylase recruitment, a number ofgenes implicated in multilineage blood cell development . Involved in CIART-mediated transcriptional repression ofthe circadian transcriptional activator: CLOCK-BMAL1 heterodimer . Required for the transcriptional repression of circadiantarget genes, such as PER1, mediated by the large PER complex or CRY1through histone deacetylation . In addition to proteindeacetylase activity, also has protein-lysine deacylase activity: actsas a protein decrotonylase and delactylase by mediating decrotonylation-butenoyl) and delactylation of histones, respectively. {ECO:0000250|UniProtKB:O09106,ECO:0000269|PubMed:12837748, ECO:0000269|PubMed:16285960,ECO:0000269|PubMed:16428440, ECO:0000269|PubMed:16478997,ECO:0000269|PubMed:16762839, ECO:0000269|PubMed:17000776,ECO:0000269|PubMed:17704056, ECO:0000269|PubMed:17996965,ECO:0000269|PubMed:19081374, ECO:0000269|PubMed:19343227,ECO:0000269|PubMed:21041482, ECO:0000269|PubMed:28497810,ECO:0000269|PubMed:28977666, ECO:0000269|PubMed:35044827}.
• Uniprot ID: HDAC1_HUMAN
• Ensembl ID: ENSG0000011647813
• HGNC ID: HGNC:4852

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Drug

Investigative Drug(s) 2 drug(s) in total

IMC-HA

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [1]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: IMC-HA
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: THP-1 cells; monocytic; Homo sapiens (Human); N.A.
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Western blot assay; Molecular docking assay
• Experiment for Drug Resistance: Cell viability assay; Apoptosis assay; Cell cycle assay; HDAC activity assay
• Mechanism Description: In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML.

IMC-OPD

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [1]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: IMC-OPD
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: THP-1 cells; monocytic; Homo sapiens (Human); N.A.
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Western blot assay; Molecular docking assay
• Experiment for Drug Resistance: Cell viability assay; Apoptosis assay; Cell cycle assay; HDAC activity assay
• Mechanism Description: In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML.

References

• Ref 1: A potent dual inhibitor targeting COX-2 and HDAC of acute myeloid leukemia cells. Mol Divers. 2025 Jun;29(3):2433-2444.