Target General Infomation
Target ID
T63816
Former ID
TTDC00159
Target Name
Histone deacetylase 4
Gene Name
HDAC4
Synonyms
HD4; Histone deacetylase 4; HDAC4
Target Type
Research
Disease Advanced stage follicular lymphoma [ICD9: 202; ICD10: C82]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Huntington's disease [ICD9: 294.1, 333.4; ICD10: F02.2, G10]
Function
Responsible forthe 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. 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.
BioChemical Class
Carbon-nitrogen hydrolase
Target Validation
T63816
UniProt ID
EC Number
EC 3.5.1.98
Sequence
MSSQSHPDGLSGRDQPVELLNPARVNHMPSTVDVATALPLQVAPSAVPMDLRLDHQFSLP
VAEPALREQQLQQELLALKQKQQIQRQILIAEFQRQHEQLSRQHEAQLHEHIKQQQEMLA
MKHQQELLEHQRKLERHRQEQELEKQHREQKLQQLKNKEKGKESAVASTEVKMKLQEFVL
NKKKALAHRNLNHCISSDPRYWYGKTQHSSLDQSSPPQSGVSTSYNHPVLGMYDAKDDFP
LRKTASEPNLKLRSRLKQKVAERRSSPLLRRKDGPVVTALKKRPLDVTDSACSSAPGSGP
SSPNNSSGSVSAENGIAPAVPSIPAETSLAHRLVAREGSAAPLPLYTSPSLPNITLGLPA
TGPSAGTAGQQDAERLTLPALQQRLSLFPGTHLTPYLSTSPLERDGGAAHSPLLQHMVLL
EQPPAQAPLVTGLGALPLHAQSLVGADRVSPSIHKLRQHRPLGRTQSAPLPQNAQALQHL
VIQQQHQQFLEKHKQQFQQQQLQMNKIIPKPSEPARQPESHPEETEEELREHQALLDEPY
LDRLPGQKEAHAQAGVQVKQEPIESDEEEAEPPREVEPGQRQPSEQELLFRQQALLLEQQ
RIHQLRNYQASMEAAGIPVSFGGHRPLSRAQSSPASATFPVSVQEPPTKPRFTTGLVYDT
LMLKHQCTCGSSSSHPEHAGRIQSIWSRLQETGLRGKCECIRGRKATLEELQTVHSEAHT
LLYGTNPLNRQKLDSKKLLGSLASVFVRLPCGGVGVDSDTIWNEVHSAGAARLAVGCVVE
LVFKVATGELKNGFAVVRPPGHHAEESTPMGFCYFNSVAVAAKLLQQRLSVSKILIVDWD
VHHGNGTQQAFYSDPSVLYMSLHRYDDGNFFPGSGAPDEVGTGPGVGFNVNMAFTGGLDP
PMGDAEYLAAFRTVVMPIASEFAPDVVLVSSGFDAVEGHPTPLGGYNLSARCFGYLTKQL
MGLAGGRIVLALEGGHDLTAICDASEACVSALLGNELDPLPEKVLQQRPNANAVRSMEKV
MEIHSKYWRCLQRTTSTAGRSLIEAQTCENEEAETVTAMASLSVGVKPAEKRPDEEPMEE
EPPL
Structure
2H8N; 2O94; 2VQJ; 2VQM; 2VQO; 2VQQ; 2VQV; 2VQW; 3UXG;3UZD; 3V31; 4CBT; 4CBY; 2H8N; 2O94; 2VQJ; 2VQM; 2VQO; 2VQQ; 2VQV; 2VQW; 3UXG; 3UZD; 3V31; 4CBT; 4CBY
Drugs and Mode of Action
Drug(s) Quisinostat Drug Info Phase 2 Advanced stage follicular lymphoma [1725891]
Inhibitor (E)-8-Biphenyl-4-yl-1-oxazol-2-yl-oct-7-en-1-one Drug Info [526871]
2,2-bis(3-fluorophenyl)-N-hydroxyacetamide Drug Info [530327]
2,2-bis(4-chlorophenyl)-N-hydroxyacetamide Drug Info [530327]
2,2-bis(4-fluorophenyl)-N-hydroxyacetamide Drug Info [530327]
2-(methylsulfonylthio)ethyl 2-propylpentanoate Drug Info [529333]
4-Benzoylamino-N-hydroxy-benzamide Drug Info [527691]
4-Butyrylamino-N-hydroxy-benzamide Drug Info [526922]
4-Chloro-N-(5-hydroxycarbamoyl-pentyl)-benzamide Drug Info [526878]
4-Dimethylamino-N-(6-mercapto-hexyl)-benzamide Drug Info [527439]
4-Hydroxy-N-(5-hydroxycarbamoyl-pentyl)-benzamide Drug Info [526266]
5-(4-Chloro-phenyl)-pentanoic acid hydroxyamide Drug Info [527056]
5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione Drug Info [529333]
5-Mercapto-pentanoic acid phenylamide Drug Info [527439]
6-(2-Bromo-acetylamino)-hexanoic acid phenylamide Drug Info [527439]
6-benzenesulfinylhexanoic acid hydroxamide Drug Info [527980]
6-benzenesulfonylhexanoic acid hydroxamide Drug Info [527980]
6-Mercapto-hexanoic acid phenylamide Drug Info [527439]
6-Phenoxy-hexane-1-thiol Drug Info [527439]
6-phenylsulfanylhexanoic acid hydroxamide Drug Info [527980]
7-(Biphenyl-3-yloxy)-1-oxazol-2-yl-heptan-1-one Drug Info [526871]
7-(Biphenyl-4-yloxy)-1,1,1-trifluoro-heptan-2-one Drug Info [526878]
7-(Biphenyl-4-yloxy)-1-oxazol-2-yl-heptan-1-one Drug Info [526871]
7-(Naphthalen-2-yloxy)-1-oxazol-2-yl-heptan-1-one Drug Info [526871]
7-Mercapto-heptanoic acid benzothiazol-2-ylamide Drug Info [527439]
7-Mercapto-heptanoic acid biphenyl-3-ylamide Drug Info [527439]
7-Mercapto-heptanoic acid biphenyl-4-ylamide Drug Info [527439]
7-Mercapto-heptanoic acid phenylamide Drug Info [527439]
7-Mercapto-heptanoic acid pyridin-3-ylamide Drug Info [527439]
7-Mercapto-heptanoic acid quinolin-3-ylamide Drug Info [527439]
7-mercapto-N-(4-phenylthiazol-2-yl)heptanamide Drug Info [529093]
8-(Biphenyl-4-yloxy)-1,1,1-trifluoro-octan-2-one Drug Info [526871]
8-Mercapto-octanoic acid phenylamide Drug Info [527439]
8-Oxo-8-phenyl-octanoic acid Drug Info [526266]
8-Oxo-8-phenyl-octanoic acid hydroxyamide Drug Info [526878]
9,9,9-Trifluoro-8-oxo-nonanoic acid phenylamide Drug Info [526878]
9-(Biphenyl-4-yloxy)-1,1,1-trifluoro-nonan-2-one Drug Info [526878]
AZUMAMIDE B Drug Info [529411]
AZUMAMIDE C Drug Info [529411]
AZUMAMIDE E Drug Info [529411]
Cyclo(-L-Am7(S2Py)-A2in-L-Ala-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Ala-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Ala-D-Tic-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Ph4-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Ph5-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Phe-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Phg-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Ser(Bzl)-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-Aib-L-Ser-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-D-2MePhe-L-Ala-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-D-A1in-L-Ala-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-L-2MePhe-L-Ala-D-Pro-) Drug Info [529054]
Cyclo(-L-Am7(S2Py)-L-A1in-L-Ala-D-Pro-) Drug Info [529054]
Cyclostellettamine derivative Drug Info [527058]
LARGAZOLE Drug Info [530933]
N-(2-Mercapto-ethyl)-N'-phenyl-oxalamide Drug Info [527500]
N-(2-Mercapto-ethyl)-N'-phenyl-succinamide Drug Info [527500]
N-(5-Hydroxycarbamoyl-pentyl)-4-nitro-benzamide Drug Info [526878]
N-(6-Hydroxycarbamoyl-hexyl)-benzamide Drug Info [526266]
N-(6-Mercapto-hexyl)-benzamide Drug Info [527439]
N-hydroxy-2,2-diphenylacetamide Drug Info [530327]
N-hydroxy-2,2-diphenylpropanamide Drug Info [530327]
N-Hydroxy-4-((R)-2-phenyl-butyrylamino)-benzamide Drug Info [527691]
N-Hydroxy-4-((S)-2-phenyl-butyrylamino)-benzamide Drug Info [527691]
N-Hydroxy-4-(2-phenyl-butyrylamino)-benzamide Drug Info [527691]
N-Hydroxy-4-(3-phenyl-propionylamino)-benzamide Drug Info [527691]
N-Hydroxy-4-(4-phenyl-butyrylamino)-benzamide Drug Info [527691]
N-Hydroxy-4-(5-phenyl-pentanoylamino)-benzamide Drug Info [527691]
N-Hydroxy-4-(pentanoylamino-methyl)-benzamide Drug Info [526922]
N-Hydroxy-4-(phenylacetylamino-methyl)-benzamide Drug Info [526922]
N-Hydroxy-4-phenylacetylamino-benzamide Drug Info [527691]
N-hydroxy-9,10-dihydroanthracene-9-carboxamide Drug Info [530327]
N-hydroxy-9H-xanthene-9-carboxamide Drug Info [530327]
Octanedioic acid bis-hydroxyamide Drug Info [526376]
Octanedioic acid hydroxyamide pyridin-2-ylamide Drug Info [526266]
Octanedioic acid hydroxyamide pyridin-4-ylamide Drug Info [526266]
PSAMMAPLIN A Drug Info [526878]
Quisinostat Drug Info [1725887]
santacruzamate A Drug Info [532523]
ST-2987 Drug Info [530016]
ST-3050 Drug Info [530016]
Thioacetic acid S-(6-phenylcarbamoyl-hexyl) ester Drug Info [527439]
TMP269 Drug Info [532282]
Modulator HDAC4 inhibtors Drug Info [543681]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Alcoholism
Epstein-Barr virus infection
Viral carcinogenesis
MicroRNAs in cancer
NetPath Pathway IL2 Signaling Pathway
Pathway Interaction Database Signaling events mediated by HDAC Class II
Signaling events mediated by HDAC Class III
Signaling events mediated by HDAC Class I
Sumoylation by RanBP2 regulates transcriptional repression
Validated nuclear estrogen receptor alpha network
Reactome NOTCH1 Intracellular Domain Regulates Transcription
Constitutive Signaling by NOTCH1 PEST Domain Mutants
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
WikiPathways Endochondral Ossification
Cardiac Hypertrophic Response
Neural Crest Differentiation
miR-targeted genes in muscle cell - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in epithelium - TarBase
TarBasePathway
Cell Cycle
MicroRNAs in cardiomyocyte hypertrophy
References
Ref 1725891ClinicalTrials.gov (NCT01486277) A Study of the Histone Deacetylase Inhibitor (HDACi) Quisinostat (JNJ-26481585) in Patients With Previously Treated Stage Ib-IVa Cutaneous T-cell Lymphoma
Ref 526266J Med Chem. 2002 Feb 14;45(4):753-7.Inhibitors of human histone deacetylase: synthesis and enzyme and cellular activity of straight chain hydroxamates.
Ref 526376J Med Chem. 2002 Jul 18;45(15):3296-309.Structure-activity relationships on phenylalanine-containing inhibitors of histone deacetylase: in vitro enzyme inhibition, induction of differentiation, and inhibition of proliferation in Friend leukemic cells.
Ref 526871Bioorg Med Chem Lett. 2003 Nov 17;13(22):3909-13.Heterocyclic ketones as inhibitors of histone deacetylase.
Ref 526878J Med Chem. 2003 Nov 20;46(24):5097-116.Histone deacetylase inhibitors.
Ref 526922J Med Chem. 2004 Jan 15;47(2):467-74.Zn2+-chelating motif-tethered short-chain fatty acids as a novel class of histone deacetylase inhibitors.
Ref 527056Bioorg Med Chem Lett. 2004 May 17;14(10):2477-81.Stereodefined and polyunsaturated inhibitors of histone deacetylase based on (2E,4E)-5-arylpenta-2,4-dienoic acid hydroxyamides.
Ref 527058Bioorg Med Chem Lett. 2004 May 17;14(10):2617-20.Three new cyclostellettamines, which inhibit histone deacetylase, from a marine sponge of the genus Xestospongia.
Ref 527439J Med Chem. 2005 Feb 24;48(4):1019-32.Novel inhibitors of human histone deacetylases: design, synthesis, enzyme inhibition, and cancer cell growth inhibition of SAHA-based non-hydroxamates.
Ref 527500Bioorg Med Chem Lett. 2005 Apr 15;15(8):1969-72.Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors.
Ref 527691J Med Chem. 2005 Aug 25;48(17):5530-5.Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors.
Ref 527980J Med Chem. 2006 Jan 26;49(2):800-5.Aromatic sulfide inhibitors of histone deacetylase based on arylsulfinyl-2,4-hexadienoic acid hydroxyamides.
Ref 529054Bioorg Med Chem. 2007 Dec 15;15(24):7830-9. Epub 2007 Aug 26.Molecular design of histone deacetylase inhibitors by aromatic ring shifting in chlamydocin framework.
Ref 529093J Med Chem. 2007 Nov 1;50(22):5425-38. Epub 2007 Oct 11.Design, synthesis, structure--selectivity relationship, and effect on human cancer cells of a novel series of histone deacetylase 6-selective inhibitors.
Ref 529333Bioorg Med Chem Lett. 2008 Mar 15;18(6):1893-7. Epub 2008 Feb 8.New sulfurated derivatives of valproic acid with enhanced histone deacetylase inhibitory activity.
Ref 529411Bioorg Med Chem Lett. 2008 May 1;18(9):2982-4. Epub 2008 Mar 21.Evaluation of antiangiogenic activity of azumamides by the in vitro vascular organization model using mouse induced pluripotent stem (iPS) cells.
Ref 530016Bioorg Med Chem Lett. 2009 Apr 15;19(8):2346-9. Epub 2009 Feb 12.N-Hydroxy-(4-oxime)-cinnamide: a versatile scaffold for the synthesis of novel histone deacetylase [correction of deacetilase] (HDAC)inhibitors.
Ref 530327Bioorg Med Chem Lett. 2009 Oct 1;19(19):5684-8. Epub 2009 Aug 7.Diphenylmethylene hydroxamic acids as selective class IIa histone deacetylase inhibitors.
Ref 530933J Med Chem. 2010 Jun 24;53(12):4654-67.Synthesis and biological characterization of the histone deacetylase inhibitor largazole and C7- modified analogues.
Ref 532282Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat Chem Biol. 2013 May;9(5):319-25.
Ref 532523Santacruzamate 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 543681(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2659).
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017
Ref 1725887Wikipedia: Quisinostat

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