Target Information

Target General Infomation
Target ID
T51191
Former ID
TTDR01156
Target Name
Histone deacetylase 2
Gene Name
HDAC2
Synonyms
HDAC2
Target Type
Clinical Trial
Disease Cancer [ICD9: 140-229; ICD10: C00-C96]
Dermatitis [ICD9: 692.9; ICD10: L20-L30]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Responsible 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, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Forms transcriptional repressor complexes byassociating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation. Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A.
BioChemical Class
Carbon-nitrogen hydrolase
Target Validation
T51191
UniProt ID
Q92769
EC Number
EC 3.5.1.98
Sequence
MAYSQGGGKKKVCYYYDGDIGNYYYGQGHPMKPHRIRMTHNLLLNYGLYRKMEIYRPHKA
TAEEMTKYHSDEYIKFLRSIRPDNMSEYSKQMQRFNVGEDCPVFDGLFEFCQLSTGGSVA
GAVKLNRQQTDMAVNWAGGLHHAKKSEASGFCYVNDIVLAILELLKYHQRVLYIDIDIHH
GDGVEEAFYTTDRVMTVSFHKYGEYFPGTGDLRDIGAGKGKYYAVNFPMRDGIDDESYGQ
IFKPIISKVMEMYQPSAVVLQCGADSLSGDRLGCFNLTVKGHAKCVEVVKTFNLPLLMLG
GGGYTIRNVARCWTYETAVALDCEIPNELPYNDYFEYFGPDFKLHISPSNMTNQNTPEYM
EKIKQRLFENLRMLPHAPGVQMQAIPEDAVHEDSGDEDGEDPDKRISIRASDKRIACDEE
FSDSEDEGEGGRRNVADHKKGAKKARIEEDKKETEDKKTDVKEEDKSKDNSGEKTDTKGT
KSEQLSNP
Drugs and Mode of Action
Drug(s) CHR-3996 Drug Info Phase 1 Solid tumours [1], [2]
Inhibitor (E)-8-Biphenyl-4-yl-1-oxazol-2-yl-oct-7-en-1-one Drug Info [3]
1,1,1-Trifluoro-8-(4-phenoxy-phenoxy)-octan-2-one Drug Info [4]
1,1,1-Trifluoro-8-phenoxy-octan-2-one Drug Info [4]
2-(allyloxy)-N8-hydroxy-N1-phenyloctanediamide Drug Info [5]
2-(benzyloxy)-N7-hydroxy-N1-phenylheptanediamide Drug Info [5]
2-(methylsulfonylthio)ethyl 2-propylpentanoate Drug Info [6]
4-Benzoylamino-N-hydroxy-benzamide Drug Info [7]
4-Butyrylamino-N-hydroxy-benzamide Drug Info [8]
4-Chloro-N-(5-hydroxycarbamoyl-pentyl)-benzamide Drug Info [9]
4-Dimethylamino-N-(6-mercapto-hexyl)-benzamide Drug Info [10]
4-Hydroxy-N-(5-hydroxycarbamoyl-pentyl)-benzamide Drug Info [11]
4-Phenylbutyrohydroxamic acid Drug Info [12]
5-(4-Chloro-phenyl)-pentanoic acid hydroxyamide Drug Info [13]
5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione Drug Info [6]
5-(Biphenyl-4-yl)-pentanoic acid N-hydroxyamide Drug Info [14]
5-Mercapto-pentanoic acid phenylamide Drug Info [10]
6-(2-Bromo-acetylamino)-hexanoic acid phenylamide Drug Info [10]
6-benzenesulfinylhexanoic acid hydroxamide Drug Info [15]
6-benzenesulfonylhexanoic acid hydroxamide Drug Info [15]
6-Mercapto-hexanoic acid phenylamide Drug Info [10]
6-Phenoxy-hexane-1-thiol Drug Info [10]
6-phenylsulfanylhexanoic acid hydroxamide Drug Info [15]
7-(Biphenyl-3-yloxy)-1-oxazol-2-yl-heptan-1-one Drug Info [3]
7-(Biphenyl-4-yloxy)-1,1,1-trifluoro-heptan-2-one Drug Info [4]
7-(Biphenyl-4-yloxy)-1-oxazol-2-yl-heptan-1-one Drug Info [3]
7-(Biphenyl-4-yloxy)-heptanoic acid hydroxyamide Drug Info [16]
7-(Naphthalen-2-yloxy)-1-oxazol-2-yl-heptan-1-one Drug Info [3]
7-Biphenyl-4-yl-heptanoic acid hydroxyamide Drug Info [17]
7-Mercapto-heptanoic acid benzothiazol-2-ylamide Drug Info [10]
7-Mercapto-heptanoic acid biphenyl-3-ylamide Drug Info [10]
7-Mercapto-heptanoic acid biphenyl-4-ylamide Drug Info [10]
7-Mercapto-heptanoic acid phenylamide Drug Info [10]
7-Mercapto-heptanoic acid pyridin-3-ylamide Drug Info [10]
7-Mercapto-heptanoic acid quinolin-3-ylamide Drug Info [10]
7-Phenoxy-heptanoic acid hydroxyamide Drug Info [17]
8-(Biphenyl-3-yloxy)-1,1,1-trifluoro-octan-2-one Drug Info [4]
8-(Biphenyl-4-yloxy)-1,1,1-trifluoro-octan-2-one Drug Info [4]
8-(Biphenyl-4-yloxy)-2-oxo-octanoic acid Drug Info [16]
8-Mercapto-octanoic acid phenylamide Drug Info [10]
8-Oxo-8-phenyl-octanoic acid Drug Info [11]
8-Oxo-8-phenyl-octanoic acid hydroxyamide Drug Info [9]
8-Phenyl-octanoic acid hydroxyamide Drug Info [17]
9,9,9-Trifluoro-8-oxo-nonanoic acid phenylamide Drug Info [4]
9-(Biphenyl-4-yloxy)-1,1,1-trifluoro-nonan-2-one Drug Info [4]
CHR-3996 Drug Info [1]
Cyclostellettamine derivative Drug Info [18]
KAR-1880 Drug Info [19]
N-(2-amino-5-(benzofuran-2-yl)phenyl)benzamide Drug Info [20]
N-(2-amino-5-(furan-2-yl)phenyl)benzamide Drug Info [20]
N-(2-amino-5-(furan-3-yl)phenyl)benzamide Drug Info [20]
N-(2-amino-5-(pyridin-4-yl)phenyl)benzamide Drug Info [20]
N-(2-amino-5-(thiazol-2-yl)phenyl)benzamide Drug Info [20]
N-(2-amino-5-(thiophen-2-yl)phenyl)nicotinamide Drug Info [21]
N-(2-aminophenyl)-4-methoxybenzamide Drug Info [22]
N-(2-aminophenyl)benzamide Drug Info [20]
N-(2-aminophenyl)nicotinamide Drug Info [21]
N-(2-aminophenyl)quinoxaline-6-carboxamide Drug Info [22]
N-(2-Mercapto-ethyl)-N'-phenyl-oxalamide Drug Info [23]
N-(2-Mercapto-ethyl)-N'-phenyl-succinamide Drug Info [23]
N-(3'-acetyl-4-aminobiphenyl-3-yl)benzamide Drug Info [20]
N-(4'-acetyl-4-aminobiphenyl-3-yl)benzamide Drug Info [20]
N-(4-amino-3'-methoxybiphenyl-3-yl)benzamide Drug Info [20]
N-(4-amino-3'-methylbiphenyl-3-yl)benzamide Drug Info [20]
N-(4-amino-4'-bromobiphenyl-3-yl)benzamide Drug Info [20]
N-(4-amino-4'-fluorobiphenyl-3-yl)benzamide Drug Info [20]
N-(4-amino-4'-methoxybiphenyl-3-yl)benzamide Drug Info [20]
N-(4-amino-4'-vinylbiphenyl-3-yl)benzamide Drug Info [20]
N-(4-aminobiphenyl-3-yl)benzamide Drug Info [20]
N-(4-aminobiphenyl-3-yl)nicotinamide Drug Info [21]
N-(4-hydroxybiphenyl-3-yl)benzamide Drug Info [21]
N-(5-Hydroxycarbamoyl-pentyl)-4-nitro-benzamide Drug Info [9]
N-(6-Hydroxycarbamoyl-hexyl)-benzamide Drug Info [11]
N-(6-Mercapto-hexyl)-benzamide Drug Info [10]
N-Hydroxy-4-((R)-2-phenyl-butyrylamino)-benzamide Drug Info [7]
N-Hydroxy-4-((S)-2-phenyl-butyrylamino)-benzamide Drug Info [7]
N-Hydroxy-4-(2-phenyl-butyrylamino)-benzamide Drug Info [7]
N-Hydroxy-4-(3-phenyl-propionylamino)-benzamide Drug Info [24]
N-Hydroxy-4-(4-phenyl-butyrylamino)-benzamide Drug Info [7]
N-Hydroxy-4-(5-phenyl-pentanoylamino)-benzamide Drug Info [7]
N-Hydroxy-4-(pentanoylamino-methyl)-benzamide Drug Info [8]
N-Hydroxy-4-(phenylacetylamino-methyl)-benzamide Drug Info [8]
N-Hydroxy-4-phenylacetylamino-benzamide Drug Info [7]
N-Hydroxy-E-3-(4'-chlorobiphenyl-4-yl)-acrylamide Drug Info [14]
N-Hydroxy-E-3-(4'-cyanobiphenyl-4-yl)-acrylamide Drug Info [14]
N-Hydroxy-E-3-(biphenyl-4-yl)-acrylamide Drug Info [14]
N7-hydroxy-2-methoxy-N1-phenylheptanediamide Drug Info [5]
N7-hydroxy-N1-phenyl-2-propoxyheptanediamide Drug Info [5]
N8,2-dihydroxy-N1-phenyloctanediamide Drug Info [5]
N8-hydroxy-2-methoxy-N1-phenyloctanediamide Drug Info [5]
Octanedioic acid bis-hydroxyamide Drug Info [25]
Octanedioic acid hydroxyamide pyridin-2-ylamide Drug Info [11]
Octanedioic acid hydroxyamide pyridin-4-ylamide Drug Info [11]
PSAMMAPLIN A Drug Info [9]
santacruzamate A Drug Info [26]
ST-2986 Drug Info [27]
ST-2987 Drug Info [27]
Thioacetic acid S-(6-phenylcarbamoyl-hexyl) ester Drug Info [10]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Cell cycle
Notch signaling pathway
Thyroid hormone signaling pathway
Huntington&#039
s disease
Alcoholism
Epstein-Barr virus infection
Pathways in cancer
Transcriptional misregulation in cancer
Viral carcinogenesis
Chronic myeloid leukemia
NetPath Pathway TCR Signaling Pathway
PANTHER Pathway Wnt signaling pathway
Pathway Interaction Database Regulation of nuclear SMAD2/3 signaling
Signaling events mediated by HDAC Class I
Regulation of Telomerase
Glucocorticoid receptor regulatory network
Direct p53 effectors
Hedgehog signaling events mediated by Gli proteins
Regulation of nuclear beta catenin signaling and target gene transcription
Reactome p75NTR negatively regulates cell cycle via SC1
NOTCH1 Intracellular Domain Regulates Transcription
Constitutive Signaling by NOTCH1 PEST Domain Mutants
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
HDACs deacetylate histones
NoRC negatively regulates rRNA expression
RNA Polymerase I Transcription Initiation
Factors involved in megakaryocyte development and platelet production
WikiPathways Notch Signaling Pathway
Notch Signaling Pathway
Neural Crest Differentiation
Signalling by NGF
RNA Polymerase I, RNA Polymerase III, and Mitochondrial Transcription
Factors involved in megakaryocyte development and platelet production
Cell Cycle
References
REF 1A 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(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. (Ligand id: 8391).
REF 3Bioorg Med Chem Lett. 2003 Nov 17;13(22):3909-13.Heterocyclic ketones as inhibitors of histone deacetylase.
REF 4Bioorg Med Chem Lett. 2002 Dec 2;12(23):3443-7.Trifluoromethyl ketones as inhibitors of histone deacetylase.
REF 5Bioorg Med Chem Lett. 2007 Nov 15;17(22):6261-5. Epub 2007 Sep 8.Omega-alkoxy analogues of SAHA (vorinostat) as inhibitors of HDAC: a study of chain-length and stereochemical dependence.
REF 6Bioorg 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 7J Med Chem. 2005 Aug 25;48(17):5530-5.Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors.
REF 8J 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 9J Med Chem. 2003 Nov 20;46(24):5097-116.Histone deacetylase inhibitors.
REF 10J 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 11J 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 12Nat Chem Biol. 2010 Mar;6(3):238-243. Epub 2010 Feb 7.Chemical phylogenetics of histone deacetylases.
REF 13Bioorg 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 14Eur J Med Chem. 2009 May;44(5):1900-12. Epub 2008 Nov 19.Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors.
REF 15J Med Chem. 2006 Jan 26;49(2):800-5.Aromatic sulfide inhibitors of histone deacetylase based on arylsulfinyl-2,4-hexadienoic acid hydroxyamides.
REF 16Bioorg Med Chem Lett. 2003 Oct 6;13(19):3331-5.Alpha-keto amides as inhibitors of histone deacetylase.
REF 17Bioorg Med Chem Lett. 2003 Nov 3;13(21):3817-20.A novel series of histone deacetylase inhibitors incorporating hetero aromatic ring systems as connection units.
REF 18Bioorg 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 19(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: 2616).
REF 20Bioorg Med Chem Lett. 2010 May 15;20(10):3142-5. Epub 2010 Mar 30.Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N-(2-aminophenyl)benzamides.
REF 21Bioorg Med Chem Lett. 2008 Dec 1;18(23):6104-9. Epub 2008 Oct 14.SAR profiles of spirocyclic nicotinamide derived selective HDAC1/HDAC2 inhibitors (SHI-1:2).
REF 22J Med Chem. 2007 Nov 15;50(23):5543-6. Epub 2007 Oct 17.Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
REF 23Bioorg Med Chem Lett. 2005 Apr 15;15(8):1969-72.Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors.
REF 24Eur J Med Chem. 2009 Nov;44(11):4470-6. Epub 2009 Jun 17.Design, synthesis and preliminary biological evaluation of N-hydroxy-4-(3-phenylpropanamido)benzamide (HPPB) derivatives as novel histone deacetylase inhibitors.
REF 25J 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 26Santacruzamate 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 27Bioorg 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.

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