Therapeutic Targets Database
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TTD Target ID: TTDC00159

Target Information
NameHistone deacetylase 4    
Type of targetClinical trial target    
SynonymsHDAC4    
DiseaseAcne
[ICD9: 706.1   ICD10: L70.0]
[1][2]
Basal cell carcinoma
[ICD9: 173   ICD10: C44]
[1][2]
Bladder cancer
[ICD9: 188   ICD10: C67]
[3][4][5]
Colorectal Cancer
[ICD9: 153, 154   ICD10: C18-C21]
[3][4][5]
Cutaneous T-Cell Lymphoma
[ICD9: 202.1, 202.2   ICD10: C84.0, C84.1]
[6][7][8]
Leukemia, Lymphoid
[ICD9: 208.9   ICD10: C91-C95]
[6][7][8]
Leukemia, Myeloid
[ICD9: 208.9   ICD10: C91-C95]
[6][7][8]
Liver Cancer
[ICD9: 155   ICD10: C22.0]
[3][4][5]
Lymphoma, Unspecified
[ICD9: 202.8   ICD10: C81-C96]
[6][7][8]
Melanoma; Prostate cancer
[ICD9: 140-229, 172, 185   ICD10: C00-C96, C43, C61]
[9][10][8]
Mesothelioma
[ICD9: 163   ICD10: C45]
[3][4][5]
Multiple Myeloma
[ICD9: 203.0   ICD10: C90.0]
[6][7][8]
Myelodysplastic Syndrome
[ICD9: 238.7   ICD10: D46]
[3][4][5]
Ovarian cancer
[ICD9: 183   ICD10: C56]
[3][4][5]
Pancreatic Cancer
[ICD9: 157   ICD10: C25]
[6][7][8]
Prostate cancer
[ICD9: 185   ICD10: C61]
[6][7][8]
Prostate cancer (hormone refractory)
[ICD9: 140-229, 185   ICD10: C00-C96, C61]
[11]
Renal Cell Carcinoma
[ICD9: 189   ICD10: C64]
[6][7][8]
Sarcoma[3][4][5]
Skin cancer
[ICD9: 172, 173   ICD10: C43-C44]
[1][2]
Solid tumors
[ICD9: 140-199, 210-229   ICD10: C00-C75, C7A, C7B, D10-D36, D3A]
[6][7][8]
Drug(s)FK-228Phase IICutaneous T-Cell Lymphoma, Lymphoma, Renal Cell Carcinoma, Prostate Cancer[6][7][8][12]
FK-228Phase I/IIPancreatic Cancer, Solid Tumors, Multiple Myeloma[6][7][8][12]
FK-228Phase ILymphoid Leukemia, Myeloid Leukemia[6][7][8][12]
BioChemical ClassHydrolases acting on carbon-nitrogen bonds    
UniProt IDP56524
PDB Structure2H8N; 2O94; 2VQJ; 2VQM; 2VQO; 2VQQ; 2VQV; 2VQW; 3UXG; 3UZD; 3V31.    
FunctionResponsible for 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.    
SequenceMSSQSHPDGLSGRDQPVELLNPARVNHMPSTVDVATALPLQVAPSAVPMDLRLDHQFSLP VAEPALREQQLQQELLALKQKQQIQRQILIAEFQRQHEQLSRQHEAQLHEHIKQQQEMLA MKHQQELLEHQRKLERHRQEQELEKQHREQKLQQLKNKEKGKESAVASTEVKMKLQEFVL NKKKALAHRNLNHCISSDPRYWYGKTQHSSLDQSSPPQSGVSTSYNHPVLGMYDAKDDFP LRKTASEPNLKLRSRLKQKVAERRSSPLLRRKDGPVVTALKKRPLDVTDSACSSAPGSGP SSPNNSSGSVSAENGIAPAVPSIPAETSLAHRLVAREGSAAPLPLYTSPSLPNITLGLPA TGPSAGTAGQQDTERLTLPALQQRLSLFPGTHLTPYLSTSPLERDGGAAHSPLLQHMVLL EQPPAQAPLVTGLGALPLHAQSLVGADRVSPSIHKLRQHRPLGRTQSAPLPQNAQALQHL VIQQQHQQFLEKHKQQFQQQQLQMNKIIPKPSEPARQPESHPEETEEELREHQALLDEPY LDRLPGQKEAHAQAGVQVKQEPIESDEEEAEPPREVEPGQRQPSEQELLFRQQALLLEQQ RIHQLRNYQASMEAAGIPVSFGGHRPLSRAQSSPASATFPVSVQEPPTKPRFTTGLVYDT LMLKHQCTCGSSSSHPEHAGRIQSIWSRLQETGLRGKCECIRGRKATLEELQTVHSEAHT LLYGTNPLNRQKLDSKKLLGSLASVFVRLPCGGVGVDSDTIWNEVHSAGAARLAVGCVVE LVFKVATGELKNGFAVVRPPGHHAEESTPMGFCYFNSVAVAAKLLQQRLSVSKILIVDWD VHHGNGTQQAFYSDPSVLYMSLHRYDDGNFFPGSGAPDEVGTGPGVGFNVNMAFTGGLDP PMGDAEYLAAFRTVVMPIASEFAPDVVLVSSGFDAVEGHPTPLGGYNLSARCFGYLTKQL MGLAGGRIVLALEGGHDLTAICDASEACVSALLGNELDPLPEKVLQQRPNANAVRSMEKV MEIHSKYWRCLQRTTSTAGRSLIEAQTCENEEAETVTAMASLSVGVKPAEKRPDEEPMEE EPPL
Target ValidationClick to Find Target Validation Information.    
Inhibitor (E)-8-Biphenyl-4-yl-1-oxazol-2-yl-oct-7-en-1-one[13]
2,2-bis (3-fluorophenyl)-N-hydroxyacetamide[14]
2,2-bis (4-chlorophenyl)-N-hydroxyacetamide[14]
2,2-bis (4-fluorophenyl)-N-hydroxyacetamide[14]
2- (methylsulfonylthio)ethyl 2-propylpentanoate[15]
4-Benzoylamino-N-hydroxy-benzamide[16]
4-Butyrylamino-N-hydroxy-benzamide[17]
4-Chloro-N- (5-hydroxycarbamoyl-pentyl)-benzamide[18]
4-Dimethylamino-N- (6-mercapto-hexyl)-benzamide[19]
4-Hydroxy-N- (5-hydroxycarbamoyl-pentyl)-benzamide[20]
5- (4-Chloro-phenyl)-pentanoic acid hydroxyamide[21]
5- (4-hydroxyphenyl)-3H-1,2-dithiole-3-thione[15]
5-Mercapto-pentanoic acid phenylamide[19]
6- (2-Bromo-acetylamino)-hexanoic acid phenylamide[19]
6-Mercapto-hexanoic acid phenylamide[19]
6-Phenoxy-hexane-1-thiol[19]
6-benzenesulfinylhexanoic acid hydroxamide[22]
6-benzenesulfonylhexanoic acid hydroxamide[22]
6-phenylsulfanylhexanoic acid hydroxamide[22]
7- (Biphenyl-3-yloxy)-1-oxazol-2-yl-heptan-1-one[13]
7- (Biphenyl-4-yloxy)-1,1,1-trifluoro-heptan-2-one[18]
7- (Biphenyl-4-yloxy)-1-oxazol-2-yl-heptan-1-one[13]
7- (Naphthalen-2-yloxy)-1-oxazol-2-yl-heptan-1-one[13]
7-Mercapto-heptanoic acid benzothiazol-2-ylamide[19]
7-Mercapto-heptanoic acid biphenyl-3-ylamide[19]
7-Mercapto-heptanoic acid biphenyl-4-ylamide[19]
7-Mercapto-heptanoic acid phenylamide[19]
7-Mercapto-heptanoic acid pyridin-3-ylamide[19]
7-Mercapto-heptanoic acid quinolin-3-ylamide[19]
7-mercapto-N- (4-phenylthiazol-2-yl)heptanamide[23]
8- (Biphenyl-4-yloxy)-1,1,1-trifluoro-octan-2-one[13]
8-Mercapto-octanoic acid phenylamide[19]
8-Oxo-8-phenyl-octanoic acid[20]
8-Oxo-8-phenyl-octanoic acid hydroxyamide[18]
9,9,9-Trifluoro-8-oxo-nonanoic acid phenylamide[18]
9- (Biphenyl-4-yloxy)-1,1,1-trifluoro-nonan-2-one[18]
AZUMAMIDE B[24]
AZUMAMIDE C[24]
AZUMAMIDE E[24]
Cyclostellettamine derivative[25]
FK-228[6][7][8][12]
LARGAZOLE[26]
N- (2-Mercapto-ethyl)-N'-phenyl-oxalamide[27]
N- (2-Mercapto-ethyl)-N'-phenyl-succinamide[27]
N- (5-Hydroxycarbamoyl-pentyl)-4-nitro-benzamide[18]
N- (6-Hydroxycarbamoyl-hexyl)-benzamide[20]
N- (6-Mercapto-hexyl)-benzamide[19]
N-Hydroxy-4- ([16]
N-Hydroxy-4- ([16]
N-Hydroxy-4- (2-phenyl-butyrylamino)-benzamide[16]
N-Hydroxy-4- (3-phenyl-propionylamino)-benzamide[16]
N-Hydroxy-4- (4-phenyl-butyrylamino)-benzamide[16]
N-Hydroxy-4- (5-phenyl-pentanoylamino)-benzamide[16]
N-Hydroxy-4- (pentanoylamino-methyl)-benzamide[17]
N-Hydroxy-4- (phenylacetylamino-methyl)-benzamide[17]
N-Hydroxy-4-phenylacetylamino-benzamide[16]
N-hydroxy-2,2-diphenylacetamide[14]
N-hydroxy-2,2-diphenylpropanamide[14]
N-hydroxy-9,10-dihydroanthracene-9-carboxamide[14]
N-hydroxy-9H-xanthene-9-carboxamide[14]
Octanedioic acid bis-hydroxyamide[28]
Octanedioic acid hydroxyamide pyridin-2-ylamide[20]
Octanedioic acid hydroxyamide pyridin-4-ylamide[20]
PSAMMAPLIN A[18]
ST-2987[29]
ST-3050[29]
Thioacetic acid S- (6-phenylcarbamoyl-hexyl) ester[19]
cyclo (-L-Am7[30]
cyclo (-L-Am7[30]
cyclo (-L-Am7[30]
cyclo (-L-Am7[30]
cyclo (-L-Am7[30]
cyclo (-L-Am7[30]
cyclo (-L-Am7[30]
cyclo (-L-Am7[30]
cyclo (-L-Am7[30]
cyclo (-L-Am7[30]
cyclo (-L-Am7[30]
cyclo (-L-Am7[30]
cyclo (-L-Am7[30]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Deacetylase inhibition increases regulatory T cell function and decreases incidence and severity of collagen-induced arthritis. Exp Mol Pathol. 2009 Jul 3. [Epub ahead of print] To Reference
Ref 2HDAC inhibitor valproic acid enhances tumour cell kill in adenovirus-HSVtk mediated suicide gene therapy in HNSCC xenograft mouse model. Int J Cancer. 2009 Jun 30. [Epub ahead of print] To Reference
Ref 3Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo. Br J Cancer. 2009 Mar 10;100(5):758-63. To Reference
Ref 4The preclinical activity of the histone deacetylase inhibitor PXD101 (belinostat) in hepatocellular carcinoma cell lines. Invest New Drugs. 2009 Jan 27. [Epub ahead of print] To Reference
Ref 5Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma. J Thorac Oncol. 2009 Jan;4(1):97-101. To Reference
Ref 6Acquired vorinostat resistance shows partial cross-resistance to 'second-generation' HDAC inhibitors and correlates with loss of histone acetylation and apoptosis but not with altered HDAC and HAT activities. Anticancer Drugs. 2009 Jun;20(5):321-33. To Reference
Ref 7Histone deacetylase inhibitors: apoptotic effects and clinical implications (Review). Int J Oncol. 2008 Oct;33(4):637-46. To Reference
Ref 8Cell Res. 2007 Mar;17(3):195-211.HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics. To Reference
Ref 9Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis. Mol Cancer Ther. 2009 May 5. [Epub ahead of print] To Reference
Ref 10Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors. Cell Immunol. 2009;257(1-2):97-104. Epub 2009 Apr 8. To Reference
Ref 11Nuclear accumulation of histone deacetylase 4 (HDAC4) coincides with the loss of androgen sensitivity in hormone refractory cancer of the prostate. Eur Urol. 2004 Mar;45(3):382-9; author reply 389. To Reference
Ref 12Nat Rev Drug Discov. 2006 Sep;5(9):769-84.Anticancer activities of histone deacetylase inhibitors. To Reference
Ref 13Bioorg Med Chem Lett. 2003 Nov 17;13(22):3909-13.Heterocyclic ketones as inhibitors of histone deacetylase. To Reference
Ref 14Bioorg Med Chem Lett. 2009 Oct 1;19(19):5684-8. Epub 2009 Aug 7.Diphenylmethylene hydroxamic acids as selective class IIa histone deacetylase inhibitors. To Reference
Ref 15Bioorg 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. To Reference
Ref 16J Med Chem. 2005 Aug 25;48(17):5530-5.Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors. To Reference
Ref 17J 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. To Reference
Ref 18J Med Chem. 2003 Nov 20;46(24):5097-116.Histone deacetylase inhibitors. To Reference
Ref 19J 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. To Reference
Ref 20J Med Chem. 2002 Feb 14;45(4):753-7.Inhibitors of human histone deacetylase: synthesis and enzyme and cellular activity of straight chain hydroxamates. To Reference
Ref 21Bioorg 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. To Reference
Ref 22J Med Chem. 2006 Jan 26;49(2):800-5.Aromatic sulfide inhibitors of histone deacetylase based on arylsulfinyl-2,4-hexadienoic acid hydroxyamides. To Reference
Ref 23J 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. To Reference
Ref 24Bioorg 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. To Reference
Ref 25Bioorg 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. To Reference
Ref 26J Med Chem. 2010 Jun 24;53(12):4654-67.Synthesis and biological characterization of the histone deacetylase inhibitor largazole and C7- modified analogues. To Reference
Ref 27Bioorg Med Chem Lett. 2005 Apr 15;15(8):1969-72.Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors. To Reference
Ref 28J 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. To Reference
Ref 29Bioorg 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. To Reference
Ref 30Bioorg 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. To Reference



 

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Professor in Department of Pharmacy
National University of Singapore, Singapore


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