Target Validation Information
TTD ID T65755
Target Name Histone deacetylase (HDAC)
Type of Target
Successful
Drug Potency against Target Valproate Drug Info IC50 = 1mM [22]
AN-9 Drug Info IC50 = 1000 nM [22]
ITF2357 Drug Info IC50 = 7.5~16 nM [30]
MGCD-0103 Drug Info IC50 = 100 nM [29]
NVP-LAQ824 Drug Info IC50 = 32 nM [21]
NVP-LAQ824 Drug Info IC50 = 1 nM [22]
Panobinostat Drug Info IC50 = 1 nM [22]
PDX-101 Drug Info IC50 = 27 nM [22]
PDX-101 Drug Info Pki = 8.5 [34]
Phenylbutyrate Drug Info IC50 = 44 nM [10]
Pyroxamide Drug Info IC50 = 1 uM [22]
Romidepsin Drug Info IC50 = 36~47 nM [23]
SNDX-275 Drug Info IC50 = 300 nM [22]
Sodium butyrate Drug Info IC50 = 1000 nM [32]
Tacedinaline Drug Info IC50 = 1000 nM [22]
AR-42 Drug Info IC50 = 16 nM [28]
Chlamydocin Drug Info IC50 = 1.3 nM [25]
Depudecin Drug Info IC50 = 1000 nM [22]
HC-Toxin Drug Info IC50 = 30 nM [26]
M-carboxycinnamic acid bishydroxamide Drug Info IC50 = 1000 nM [22]
Oxamflatin Drug Info IC50 = 1000 nM [22]
SB-623 Drug Info IC50 < 10 nM [22]
SB-639 Drug Info IC50 < 10 nM [27]
Scriptaid Drug Info pKi = 6.65 [31]
SK-7041 Drug Info IC50 = 1 nM [22]
SK-7068 Drug Info IC50 = 1 nM [22]
(E)-8-Biphenyl-4-yl-1-oxazol-2-yl-oct-7-en-1-one Drug Info IC50 = 990 nM [3]
2,2-bis(3-fluorophenyl)-N-hydroxyacetamide Drug Info IC50 = 90 nM [18]
2,2-bis(4-chlorophenyl)-N-hydroxyacetamide Drug Info IC50 = 1400 nM [18]
2,2-bis(4-fluorophenyl)-N-hydroxyacetamide Drug Info IC50 = 280 nM [18]
2-(methylsulfonylthio)ethyl 2-propylpentanoate Drug Info IC50 = 9600 nM [13]
4-Benzoylamino-N-hydroxy-benzamide Drug Info IC50 = 210 nM [10]
4-Butyrylamino-N-hydroxy-benzamide Drug Info IC50 = 1500 nM [5]
4-Chloro-N-(5-hydroxycarbamoyl-pentyl)-benzamide Drug Info IC50 = 369 nM [2]
4-Dimethylamino-N-(6-mercapto-hexyl)-benzamide Drug Info IC50 = 610 nM [8]
4-Hydroxy-N-(5-hydroxycarbamoyl-pentyl)-benzamide Drug Info IC50 = 149 nM [2]
4-Phenylbutyrohydroxamic acid Drug Info Ki = 16000 nM [19]
5-(4-Chloro-phenyl)-pentanoic acid hydroxyamide Drug Info IC50 = 2580 nM [6]
5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione Drug Info IC50 = 450 nM [13]
5-Mercapto-pentanoic acid phenylamide Drug Info IC50 = 6200 nM [8]
6-benzenesulfinylhexanoic acid hydroxamide Drug Info IC50 = 7700 nM [11]
6-benzenesulfonylhexanoic acid hydroxamide Drug Info IC50 = 15500 nM [11]
6-Mercapto-hexanoic acid phenylamide Drug Info IC50 = 370 nM [8]
6-Phenoxy-hexane-1-thiol Drug Info IC50 = 11000 nM [8]
6-phenylsulfanylhexanoic acid hydroxamide Drug Info IC50 = 9400 nM [11]
7-(Biphenyl-3-yloxy)-1-oxazol-2-yl-heptan-1-one Drug Info IC50 = 620 nM [3]
7-(Biphenyl-4-yloxy)-1,1,1-trifluoro-heptan-2-one Drug Info IC50 = 2600 nM [4]
7-(Biphenyl-4-yloxy)-1-oxazol-2-yl-heptan-1-one Drug Info IC50 = 1100 nM [3]
7-(Naphthalen-2-yloxy)-1-oxazol-2-yl-heptan-1-one Drug Info IC50 = 520 nM [3]
7-Mercapto-heptanoic acid benzothiazol-2-ylamide Drug Info IC50 = 340 nM [8]
7-Mercapto-heptanoic acid biphenyl-3-ylamide Drug Info IC50 = 75 nM [8]
7-Mercapto-heptanoic acid biphenyl-4-ylamide Drug Info IC50 = 1100 nM [8]
7-Mercapto-heptanoic acid pyridin-3-ylamide Drug Info IC50 = 110 nM [8]
7-Mercapto-heptanoic acid quinolin-3-ylamide Drug Info IC50 = 72 nM [8]
8-(Biphenyl-4-yloxy)-1,1,1-trifluoro-octan-2-one Drug Info IC50 = 2900 nM [3]
8-Mercapto-octanoic acid phenylamide Drug Info IC50 = 1500 nM [8]
8-Oxo-8-phenyl-octanoic acid Drug Info IC50 = 270 nM [2]
9,9,9-Trifluoro-8-oxo-nonanoic acid phenylamide Drug Info IC50 = 6700 nM [4]
Cyclostellettamine derivative Drug Info IC50 = 17000 nM [7]
N-(2,3-Dimethylphenyl)-N'-hydroxyoctanediamide Drug Info IC50 = 1750 nM [20]
N-(2,4-Dimethylphenyl)-N'-hydroxyoctanediamide Drug Info IC50 = 1100 nM [20]
N-(2,5-Dimethylphenyl)-N'-hydroxyoctanediamide Drug Info IC50 = 1346 nM [20]
N-(2,6-Dimethylphenyl)-N'-hydroxyoctanediamide Drug Info IC50 = 4989 nM [20]
N-(2-amino-5-(thiophen-2-yl)phenyl)nicotinamide Drug Info IC50 = 7300 nM [14]
N-(2-aminophenyl)-4-methoxybenzamide Drug Info IC50 = 1400 nM [12]
N-(2-aminophenyl)nicotinamide Drug Info IC50 = 3640 nM [14]
N-(2-Ethylphenyl)-N'-hydroxyoctanediamide Drug Info IC50 = 2263 nM [20]
N-(2-Mercapto-ethyl)-N'-phenyl-oxalamide Drug Info IC50 = 2800 nM [9]
N-(2-Mercapto-ethyl)-N'-phenyl-succinamide Drug Info IC50 = 12500 nM [9]
N-(3,4-Dimethylphenyl)-N'-hydroxyoctanediamide Drug Info IC50 = 56 nM [20]
N-(3,5-Dimethylphenyl)-N'-hydroxyoctanediamide Drug Info IC50 = 30 nM [20]
N-(3-Ethylphenyl)-N'-hydroxyoctanediamide Drug Info IC50 = 35 nM [20]
N-(4-aminobiphenyl-3-yl)nicotinamide Drug Info IC50 = 11350 nM [14]
N-(4-Ethylphenyl)-N'-hydroxyoctanediamide Drug Info IC50 = 240 nM [20]
N-(5-Hydroxycarbamoyl-pentyl)-4-methoxy-benzamide Drug Info IC50 = 140 nM [1]
N-(5-Hydroxycarbamoyl-pentyl)-4-nitro-benzamide Drug Info IC50 = 1556 nM [2]
N-(5-Hydroxycarbamoyl-pentyl)-benzamide Drug Info IC50 = 900 nM [1]
N-(6-Hydroxycarbamoyl-hexyl)-benzamide Drug Info IC50 = 568 nM [2]
N-(6-Mercapto-hexyl)-benzamide Drug Info IC50 = 360 nM [8]
N-hydroxy-2,2-diphenylacetamide Drug Info IC50 = 140 nM [18]
N-hydroxy-2,2-diphenylpropanamide Drug Info IC50 = 1200 nM [18]
N-Hydroxy-4-((R)-2-phenyl-butyrylamino)-benzamide Drug Info IC50 = 68 nM [10]
N-Hydroxy-4-((S)-2-phenyl-butyrylamino)-benzamide Drug Info IC50 = 34 nM [10]
N-Hydroxy-4-(2-phenyl-butyrylamino)-benzamide Drug Info IC50 = 54 nM [10]
N-Hydroxy-4-(3-phenyl-propionylamino)-benzamide Drug Info IC50 = 110 nM [10]
N-Hydroxy-4-(4-phenyl-butyrylamino)-benzamide Drug Info IC50 = 44 nM [10]
N-Hydroxy-4-(5-phenyl-pentanoylamino)-benzamide Drug Info IC50 = 250 nM [10]
N-Hydroxy-4-(pentanoylamino-methyl)-benzamide Drug Info IC50 = 3600 nM [5]
N-Hydroxy-4-(phenylacetylamino-methyl)-benzamide Drug Info IC50 = 2500 nM [5]
N-Hydroxy-4-phenylacetylamino-benzamide Drug Info IC50 = 157 nM [10]
N-hydroxy-9,10-dihydroanthracene-9-carboxamide Drug Info IC50 = 1460 nM [18]
N-hydroxy-9H-xanthene-9-carboxamide Drug Info IC50 = 110 nM [18]
N-Hydroxy-N'-(2-methylphenyl)octanediamide Drug Info IC50 = 1348 nM [20]
N-Hydroxy-N'-(3-methylphenyl)octanediamide Drug Info IC50 = 58 nM [20]
N-Hydroxy-N'-(4-methoxyphenyl)octanediamide Drug Info IC50 = 137 nM [20]
N-Hydroxy-N'-(4-methylphenyl)octanediamide Drug Info IC50 = 114 nM [20]
N1-(biphenyl-4-yl)-N8-hydroxyoctanediamide Drug Info IC50 = 7 nM [17]
Octanedioic acid bis-hydroxyamide Drug Info Ki = 9500 nM [19]
Octanedioic acid hydroxyamide pyridin-2-ylamide Drug Info IC50 = 248 nM [2]
Octanedioic acid hydroxyamide pyridin-4-ylamide Drug Info IC50 = 306 nM [2]
PSAMMAPLIN A Drug Info IC50 = 4 nM [4]
ST-2986 Drug Info IC50 = 5480 nM [15]
ST-2987 Drug Info IC50 = 790 nM [15]
ST-3050 Drug Info IC50 = 3060 nM [15]
ST-5732 Drug Info IC50 = 18000 nM [16]
Tacedinaline Drug Info Ki = 550 nM [19]
Action against Disease Model Valproate Drug Info Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown. We report that valproic acid activates Wntdependent gene expression, similar to lithi uM, the mainstay of therapy for bipolar disorder. Valproic acid, however, acts through a distinct pathway that involves direct inhibition of histone deacetylase (IC(50) for HDAC1 = 0.4 mm). At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and endogenous promoters. Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription. Based on these observations, we propose that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproic acid in the treatment of bipolar disorder. [24]
ITF2357 Drug Info The clonogenic activity of JAK2V617F mutated cells was inhibited by low concentrations of ITF2357 (IC50 0.001-0.01 mu M) [33]
References
REF 1 Amide analogues of trichostatin A as inhibitors of histone deacetylase and inducers of terminal cell differentiation. J Med Chem. 1999 Nov 4;42(22):4669-79.
REF 2 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 3 Heterocyclic ketones as inhibitors of histone deacetylase. Bioorg Med Chem Lett. 2003 Nov 17;13(22):3909-13.
REF 4 Histone deacetylase inhibitors. J Med Chem. 2003 Nov 20;46(24):5097-116.
REF 5 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 6 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 7 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 8 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 9 Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors. Bioorg Med Chem Lett. 2005 Apr 15;15(8):1969-72.
REF 10 Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors. J Med Chem. 2005 Aug 25;48(17):5530-5.
REF 11 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 12 Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity. J Med Chem. 2007 Nov 15;50(23):5543-6.
REF 13 New sulfurated derivatives of valproic acid with enhanced histone deacetylase inhibitory activity. Bioorg Med Chem Lett. 2008 Mar 15;18(6):1893-7.
REF 14 Bioorg 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 15 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 16 Exploring bis-(indolyl)methane moiety as an alternative and innovative CAP group in the design of histone deacetylase (HDAC) inhibitors. Bioorg Med Chem Lett. 2009 May 15;19(10):2840-3.
REF 17 Isoxazole moiety in the linker region of HDAC inhibitors adjacent to the Zn-chelating group: effects on HDAC biology and antiproliferative activity. Bioorg Med Chem Lett. 2009 Jun 1;19(11):3023-6.
REF 18 Diphenylmethylene hydroxamic acids as selective class IIa histone deacetylase inhibitors. Bioorg Med Chem Lett. 2009 Oct 1;19(19):5684-8.
REF 19 Chemical phylogenetics of histone deacetylases. Nat Chem Biol. 2010 Mar;6(3):238-243.
REF 20 Biological and biophysical properties of the histone deacetylase inhibitor suberoylanilide hydroxamic acid are affected by the presence of short al... J Med Chem. 2010 Mar 11;53(5):1937-50.
REF 21 NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood. 2003 Oct 1;102(7):2615-22.
REF 22 Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006 Sep;5(9):769-84.
REF 23 HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics. Cell Res. 2007 Mar;17(3):195-211.
REF 24 Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001 Sep 28;276(39):36734-41.
REF 25 Inhibition of histone deacetylases by chlamydocin induces apoptosis and proteasome-mediated degradation of survivin. J Pharmacol Exp Ther. 2003 Feb;304(2):881-8.
REF 26 Antiproliferative effect of trichostatin A and HC-toxin in T47D human breast cancer cells. Arch Pharm Res. 2004 Jun;27(6):640-5.
REF 27 Histone deacetylase inhibitors. Eur J Med Chem. 2005 Jan;40(1):1-13.
REF 28 Novel HDAC inhibitors with radiosensitizing properties. Radiat Res. 2005 May;163(5):488-93.
REF 29 Positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (mGluR2). Curr Top Med Chem. 2005;5(9):869-84.
REF 30 The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med. 2005 Jan-Dec;11(1-12):1-15.
REF 31 Agonists and antagonists targeting the different alpha2-adrenoceptor subtypes. Curr Top Med Chem. 2007;7(2):163-86.
REF 32 Scriptaid and suberoylanilide hydroxamic acid are histone deacetylase inhibitors with potent anti-Toxoplasma gondii activity in vitro. J Parasitol. 2007 Jun;93(3):694-700.
REF 33 The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F). Leukemia. 2008 Apr;22(4):740-7.
REF 34 5-HT1A receptor, an old target for new therapeutic agents. Curr Top Med Chem. 2008;8(12):1024-34.

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