Target Information
| Target General Information | Top | |||||
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| Target ID |
T05090
(Former ID: TTDI01956)
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| Target Name |
Histone deacetylase 3 (HDAC3)
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| Synonyms |
SMAP45; RPD32; RPD3-2; HD3
Click to Show/Hide
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| Gene Name |
HDAC3
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Lymphoma [ICD-11: 2A80-2A86] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
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. Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys-27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor. Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation. Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress. Regulates both the transcriptional activation and repression phases of the circadian clock in a deacetylase activity-independent manner. During the activation phase, promotes the accumulation of ubiquitinated ARNTL/BMAL1 at the E-boxes and during the repression phase, blocks FBXL3-mediated CRY1/2 ubiquitination and promotes the interaction of CRY1 and ARNTL/BMAL1. The NCOR1-HDAC3 complex regulates the circadian expression of the core clock gene ARTNL/BMAL1 and the genes involved in lipid metabolism in the liver. Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates.
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| BioChemical Class |
Carbon-nitrogen hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.5.1.98
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| Sequence |
MAKTVAYFYDPDVGNFHYGAGHPMKPHRLALTHSLVLHYGLYKKMIVFKPYQASQHDMCR
FHSEDYIDFLQRVSPTNMQGFTKSLNAFNVGDDCPVFPGLFEFCSRYTGASLQGATQLNN KICDIAINWAGGLHHAKKFEASGFCYVNDIVIGILELLKYHPRVLYIDIDIHHGDGVQEA FYLTDRVMTVSFHKYGNYFFPGTGDMYEVGAESGRYYCLNVPLRDGIDDQSYKHLFQPVI NQVVDFYQPTCIVLQCGADSLGCDRLGCFNLSIRGHGECVEYVKSFNIPLLVLGGGGYTV RNVARCWTYETSLLVEEAISEELPYSEYFEYFAPDFTLHPDVSTRIENQNSRQYLDQIRQ TIFENLKMLNHAPSVQIHDVPADLLTYDRTDEADAEERGPEENYSRPEAPNEFYDGDHDN DKESDVEI Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T38AWT | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | CHR-3996 | Drug Info | Phase 1/2 | Lymphoma | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 17 Inhibitor drugs | + | ||||
| 1 | CHR-3996 | Drug Info | [1] | |||
| 2 | PMID29671355-Compound-11 | Drug Info | [3] | |||
| 3 | PMID29671355-Compound-21 | Drug Info | [3] | |||
| 4 | PMID29671355-Compound-25 | Drug Info | [3] | |||
| 5 | PMID29671355-Compound-31 | Drug Info | [3] | |||
| 6 | PMID29671355-Compound-43 | Drug Info | [3] | |||
| 7 | PMID29671355-Compound-44 | Drug Info | [3] | |||
| 8 | PMID29671355-Compound-55 | Drug Info | [3] | |||
| 9 | PMID29671355-Compound-56 | Drug Info | [3] | |||
| 10 | PMID29671355-Compound-59 | Drug Info | [3] | |||
| 11 | PMID29671355-Compound-61 | Drug Info | [3] | |||
| 12 | PMID29671355-Compound-62 | Drug Info | [3] | |||
| 13 | PMID29671355-Compound-67 | Drug Info | [3] | |||
| 14 | PMID29671355-Compound-8 | Drug Info | [3] | |||
| 15 | PMID29671355-Compound-9 | Drug Info | [3] | |||
| 16 | droxinostat | Drug Info | [4] | |||
| 17 | RGFP966 | Drug Info | [5] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: 1D-myo-Inositol 1,4,5,6-tetrakisphosphate | Ligand Info | |||||
| Structure Description | Structure of HDAC3 bound to corepressor and inositol tetraphosphate | PDB:4A69 | ||||
| Method | X-ray diffraction | Resolution | 2.06 Å | Mutation | No | [6] |
| PDB Sequence |
AKTVAYFYDP
11 DVGNFHYGAG21 HPMKPHRLAL31 THSLVLHYGL41 YKKMIVFKPY51 QASQHDMCRF 61 HSEDYIDFLQ71 RVSPTNMQGF81 TKSLNAFNVG91 DDCPVFPGLF101 EFCSRYTGAS 111 LQGATQLNNK121 ICDIAINWAG131 GLHHAKKFEA141 SGFCYVNDIV151 IGILELLKYH 161 PRVLYIDIDI171 HHGDGVQEAF181 YLTDRVMTVS191 FHKYGNYFFP201 GTGDMYEVGA 211 ESGRYYCLNV221 PLRDGIDDQS231 YKHLFQPVIN241 QVVDFYQPTC251 IVLQCGADSL 261 GCDRLGCFNL271 SIRGHGECVE281 YVKSFNIPLL291 VLGGGGYTVR301 NVARCWTYET 311 SLLVEEAISE321 ELPYSEYFEY331 FAPDFTLHPD341 VSTRIENQNS351 RQYLDQIRQT 361 IFENLKMLN
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Neutrophil extracellular trap formation | hsa04613 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Thyroid hormone signaling pathway | hsa04919 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 30 | Degree centrality | 3.22E-03 | Betweenness centrality | 8.60E-04 |
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| Closeness centrality | 2.49E-01 | Radiality | 1.43E+01 | Clustering coefficient | 1.77E-01 |
| Neighborhood connectivity | 4.24E+01 | Topological coefficient | 6.62E-02 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Thyroid hormone signaling pathway | |||||
| 2 | Alcoholism | |||||
| 3 | Viral carcinogenesis | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Wnt signaling pathway | |||||
| PID Pathway | [+] 5 PID Pathways | + | ||||
| 1 | Signaling events mediated by HDAC Class II | |||||
| 2 | Signaling events mediated by HDAC Class I | |||||
| 3 | Retinoic acid receptors-mediated signaling | |||||
| 4 | Validated targets of C-MYC transcriptional repression | |||||
| 5 | Regulation of retinoblastoma protein | |||||
| References | Top | |||||
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| REF 1 | A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors. Clin Cancer Res. 2012 May 1;18(9):2687-94. | |||||
| REF 2 | ClinicalTrials.gov (NCT03397706) Dose Escalation & Expansion Study of Oral VRx-3996 & Valganciclovir in Subjects With EBV-Associated Lymphoid Malignancies. U.S. National Institutes of Health. | |||||
| REF 3 | HDAC inhibitors: a 2013-2017 patent survey.Expert Opin Ther Pat. 2018 Apr 19:1-17. | |||||
| REF 4 | Selective inhibition of histone deacetylases sensitizes malignant cells to death receptor ligands. Mol Cancer Ther. 2010 Jan;9(1):246-56. | |||||
| REF 5 | HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2647-52. | |||||
| REF 6 | Structure of HDAC3 bound to co-repressor and inositol tetraphosphate. Nature. 2012 Jan 9;481(7381):335-40. | |||||
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