Target Information
| Target General Information | Top | |||||
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| Target ID |
T63816
(Former ID: TTDC00159)
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| Target Name |
Histone deacetylase 4 (HDAC4)
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| Synonyms |
KIAA0288; HD4
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| Gene Name |
HDAC4
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | 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. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Deacetylates HSPA1A and HSPA1B at 'Lys-77' leading to their preferential binding to co-chaperone STUB1. Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).
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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 |
MSSQSHPDGLSGRDQPVELLNPARVNHMPSTVDVATALPLQVAPSAVPMDLRLDHQFSLP
VAEPALREQQLQQELLALKQKQQIQRQILIAEFQRQHEQLSRQHEAQLHEHIKQQQEMLA MKHQQELLEHQRKLERHRQEQELEKQHREQKLQQLKNKEKGKESAVASTEVKMKLQEFVL NKKKALAHRNLNHCISSDPRYWYGKTQHSSLDQSSPPQSGVSTSYNHPVLGMYDAKDDFP LRKTASEPNLKLRSRLKQKVAERRSSPLLRRKDGPVVTALKKRPLDVTDSACSSAPGSGP SSPNNSSGSVSAENGIAPAVPSIPAETSLAHRLVAREGSAAPLPLYTSPSLPNITLGLPA TGPSAGTAGQQDAERLTLPALQQRLSLFPGTHLTPYLSTSPLERDGGAAHSPLLQHMVLL EQPPAQAPLVTGLGALPLHAQSLVGADRVSPSIHKLRQHRPLGRTQSAPLPQNAQALQHL VIQQQHQQFLEKHKQQFQQQQLQMNKIIPKPSEPARQPESHPEETEEELREHQALLDEPY LDRLPGQKEAHAQAGVQVKQEPIESDEEEAEPPREVEPGQRQPSEQELLFRQQALLLEQQ RIHQLRNYQASMEAAGIPVSFGGHRPLSRAQSSPASATFPVSVQEPPTKPRFTTGLVYDT LMLKHQCTCGSSSSHPEHAGRIQSIWSRLQETGLRGKCECIRGRKATLEELQTVHSEAHT LLYGTNPLNRQKLDSKKLLGSLASVFVRLPCGGVGVDSDTIWNEVHSAGAARLAVGCVVE LVFKVATGELKNGFAVVRPPGHHAEESTPMGFCYFNSVAVAAKLLQQRLSVSKILIVDWD VHHGNGTQQAFYSDPSVLYMSLHRYDDGNFFPGSGAPDEVGTGPGVGFNVNMAFTGGLDP PMGDAEYLAAFRTVVMPIASEFAPDVVLVSSGFDAVEGHPTPLGGYNLSARCFGYLTKQL MGLAGGRIVLALEGGHDLTAICDASEACVSALLGNELDPLPEKVLQQRPNANAVRSMEKV MEIHSKYWRCLQRTTSTAGRSLIEAQTCENEEAETVTAMASLSVGVKPAEKRPDEEPMEE EPPL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T63T5P | |||||
| 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: PMID29671355-Compound-47a | Ligand Info | |||||
| Structure Description | Potent, selective and CNS-penetrant tetrasubstituted cyclopropane class IIa histone deacetylase (HDAC) inhibitors | PDB:5A2S | ||||
| Method | X-ray diffraction | Resolution | 2.65 Å | Mutation | Yes | [23] |
| PDB Sequence |
TTGLVYDTLM
662 LKHQCTCGSS672 SSHPEHAGRI682 QSIWSRLQET692 GLRGKCECIR702 GRKATLEELQ 712 TVHSEAHTLL722 YGTNPANRQK732 LDSKKLLGSL742 ASVFVRLPCG752 GVGVDSDTIW 762 NEVHSAGAAR772 LAVGCVVELV782 FKVATGELKN792 GFAVVRPPGH802 HAEESTPMGF 812 CYFNSVAVAA822 KLLQQRLSVS832 KILIVDWDVH842 HGNGTQQAFY852 SDPSVLYMSL 862 HRYDDGNFFP872 GSGAPDEVGT882 GPGVGFNVNM892 AFTGGLDPPM902 GDAEYLAAFR 912 TVVMPIASEF922 APDVVLVSSG932 FDAVEGHPTP942 LGGYNLSARC952 FGYLTKQLMG 962 LAGGRIVLAL972 EGGHDLTAIC982 DASEACVSAL992 LGNELDPLPE1002 KVLQQRPNAN 1012 AVRSMEKVME1022 IHSKYWRCLQ1032
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| Ligand Name: N-Hydroxy-5-[(3-Phenyl-5,6-Dihydroimidazo[1,2-A]pyrazin-7(8h)-Yl)carbonyl]thiophene-2-Carboxamide | Ligand Info | |||||
| Structure Description | Structure of HDAC4 catalytic domain bound to a hydroxamic acid inhbitor | PDB:2VQM | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [24] |
| PDB Sequence |
PRFTTGLVYD
15 TLMLKHQCTC25 GHAGRIQSIW42 SRLQETGLRG52 KCECIRGRKA62 TLEELQTVHS 72 EAHTLLYGTN82 PLNRQKKLLG96 SLASVFVRLP106 CGGVGVDSDT116 IWNEVHSAGA 126 ARLAVGCVVE136 LVFKVATGEL146 KNGFAVVRPP156 GHHAEESTPM166 GFCYFNSVAV 176 AAKLLQQRLS186 VSKILIVDWD196 VHHGNGTQQA206 FYSDPSVLYM216 SLHRYDDGNF 226 FPGSGAPDEV236 GTGPGVGFNV246 NMAFTGGLDP256 PMGDAEYLAA266 FRTVVMPIAS 276 EFAPDVVLVS286 SGFDAVEGHP296 TPLGGYNLSA306 RCFGYLTKQL316 MGLAGGRIVL 326 ALEGGHDLTA336 ICDASEACVS346 ALLGNELDPL356 PEKVLQQRPN366 ANAVRSMEKV 376 MEIHSKYWRC386 LQRTTSTAGR396 SLIEAQTCEN406 E
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Synaptonemal complex protein 3 (SYCP3) | 25.893 (29/112) | 4.00E-03 |
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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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| Apelin signaling pathway | hsa04371 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Neutrophil extracellular trap formation | hsa04613 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 29 | Degree centrality | 3.12E-03 | Betweenness centrality | 1.73E-03 |
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| Closeness centrality | 2.44E-01 | Radiality | 1.43E+01 | Clustering coefficient | 7.14E-02 |
| Neighborhood connectivity | 3.19E+01 | Topological coefficient | 6.06E-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-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Wikipedia: Quisinostat | |||||
| REF 2 | HDAC inhibitors: a 2013-2017 patent survey.Expert Opin Ther Pat. 2018 Apr 19:1-17. | |||||
| REF 3 | Heterocyclic ketones as inhibitors of histone deacetylase. Bioorg Med Chem Lett. 2003 Nov 17;13(22):3909-13. | |||||
| REF 4 | Diphenylmethylene hydroxamic acids as selective class IIa histone deacetylase inhibitors. Bioorg Med Chem Lett. 2009 Oct 1;19(19):5684-8. | |||||
| REF 5 | New sulfurated derivatives of valproic acid with enhanced histone deacetylase inhibitory activity. Bioorg Med Chem Lett. 2008 Mar 15;18(6):1893-7. | |||||
| REF 6 | Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors. J Med Chem. 2005 Aug 25;48(17):5530-5. | |||||
| REF 7 | Zn2+-chelating motif-tethered short-chain fatty acids as a novel class of histone deacetylase inhibitors. J Med Chem. 2004 Jan 15;47(2):467-74. | |||||
| REF 8 | Histone deacetylase inhibitors. J Med Chem. 2003 Nov 20;46(24):5097-116. | |||||
| REF 9 | Novel inhibitors of human histone deacetylases: design, synthesis, enzyme inhibition, and cancer cell growth inhibition of SAHA-based non-hydroxama... J Med Chem. 2005 Feb 24;48(4):1019-32. | |||||
| REF 10 | Inhibitors of human histone deacetylase: synthesis and enzyme and cellular activity of straight chain hydroxamates. J Med Chem. 2002 Feb 14;45(4):753-7. | |||||
| REF 11 | Stereodefined and polyunsaturated inhibitors of histone deacetylase based on (2E,4E)-5-arylpenta-2,4-dienoic acid hydroxyamides. Bioorg Med Chem Lett. 2004 May 17;14(10):2477-81. | |||||
| REF 12 | Aromatic sulfide inhibitors of histone deacetylase based on arylsulfinyl-2,4-hexadienoic acid hydroxyamides. J Med Chem. 2006 Jan 26;49(2):800-5. | |||||
| REF 13 | Design, synthesis, structure--selectivity relationship, and effect on human cancer cells of a novel series of histone deacetylase 6-selective inhib... J Med Chem. 2007 Nov 1;50(22):5425-38. | |||||
| REF 14 | Evaluation of antiangiogenic activity of azumamides by the in vitro vascular organization model using mouse induced pluripotent stem (iPS) cells. Bioorg Med Chem Lett. 2008 May 1;18(9):2982-4. | |||||
| REF 15 | Molecular design of histone deacetylase inhibitors by aromatic ring shifting in chlamydocin framework. Bioorg Med Chem. 2007 Dec 15;15(24):7830-9. | |||||
| REF 16 | Three new cyclostellettamines, which inhibit histone deacetylase, from a marine sponge of the genus Xestospongia. Bioorg Med Chem Lett. 2004 May 17;14(10):2617-20. | |||||
| REF 17 | Synthesis and biological characterization of the histone deacetylase inhibitor largazole and C7- modified analogues. J Med Chem. 2010 Jun 24;53(12):4654-67. | |||||
| REF 18 | Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors. Bioorg Med Chem Lett. 2005 Apr 15;15(8):1969-72. | |||||
| REF 19 | Structure-activity relationships on phenylalanine-containing inhibitors of histone deacetylase: in vitro enzyme inhibition, induction of differenti... J Med Chem. 2002 Jul 18;45(15):3296-309. | |||||
| REF 20 | Santacruzamate A, a potent and selective histone deacetylase inhibitor from the Panamanian marine cyanobacterium cf. Symploca sp. J Nat Prod. 2013 Nov 22;76(11):2026-33. | |||||
| REF 21 | N-Hydroxy-(4-oxime)-cinnamide: a versatile scaffold for the synthesis of novel histone deacetylase [correction of deacetilase] (HDAC) inhibitors. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2346-9. | |||||
| REF 22 | Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat Chem Biol. 2013 May;9(5):319-25. | |||||
| REF 23 | Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors. ACS Med Chem Lett. 2015 Dec 10;7(1):34-9. | |||||
| REF 24 | Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain. J Biol Chem. 2008 Sep 26;283(39):26694-704. | |||||
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