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Epigenetics
Epigenetics
HDAC 抑制剂
Trichostatin A (TSA)
Trichostatin A (TSA)
目录号 S1045
Trichostatin A (TSA)是一种HDAC抑制剂，无细胞试验中IC50为1.8 nM左右。
10mM (in 1mL DMSO)
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Trichostatin A (TSA)
结构式分子量:
客户使用该产品发表的文献 20
客户使用该产品的 4 个实验数据 :
Dr. Zhang of Tianjin Medical University.
Trichostatin A (TSA)购于Selleck
质量管理及产品安全说明书
相关化合物库
Trichostatin A (TSA)
包含在以下化合物库中:
有独特属性的HDAC抑制剂
选择性强的HDAC抑制剂
HDAC3-selective, IC50=80 nM.
Rocilinostat (ACY-1215)
HDAC5-selective, IC50=5 nM.
活性最强的HDAC抑制剂
Quisinostat (JNJ-)
HDAC1, IC50=0.11 nM; HDAC2, IC50=0.33 nM.
FDA批准的HDAC抑制剂
Vorinostat (SAHA, MK0683)
Approved by FDA against cutaneous T cell lymphoma.
最新的HDAC抑制剂
RG2833 (RGFP109)
Brain-penetrant HDAC inhibitor with IC50 of 60 nM and 50 nM for HDAC1 and HDAC3, respectively.
HDAC产品比较
溶解性(25°C)
Vorinostat (SAHA, MK0683)
Entinostat (MS-275)
Panobinostat (LBH589)
Trichostatin A (TSA)
Mocetinostat (MGCD0103)
Belinostat (PXD101)
Romidepsin (FK228, Depsipeptide)
Tubastatin A HCl
Givinostat (ITF2357)
LAQ824 (Dacinostat)
Quisinostat (JNJ-HCl
Pracinostat (SB939)
Droxinostat
PCI-24781 (Abexinostat)
Rocilinostat (ACY-1215)
Valproic acid sodium salt (Sodium valproate)
CI994 (Tacedinaline)
Resminostat
RG2833 (RGFP109)
Sodium Phenylbutyrate
Tubastatin A
Nexturastat A
Tasquinimod
The catalytic domain of HDAC7 contains two distinct domains, the C-terminal domain (aa 438–912) and N-terminal domain, and the C-terminal domain of HDAC7 associates with HDAC activity. [1] HDAC7 has a novel zinc binding motif adjacent to the active site, which involves in substrate recognition and protein-protein interaction. Besides, HDAC7 also has a variant active site topology, which results in altered catalytic properties and an enlarged active site pocket. [2]
The crystal structure indicates that the aliphatic chain of Trichostatin A (TSA) fits comfortably in the narrow portion of the pocket, and makes contact with the hydrophobic groups in the pocket by van der Waals forces. The hydroxamate moiety forms hydrogen bonds with the side chains of two active site histidines (His-669 and His-670), mimicking the interactions of the water molecule in the active site of HDAC7. Besides, the hydroxyl oxygen of hydroxamate group in the inhibitor is also found to form a monodentate complex with the catalytic zinc ion due to the topology of the active site. After the binding of inhibitors, the solvent side chain of some amino acids at the periphery of the pocket changes conformation to accommodate the inhibitor TSA. [2]
References
[1] Fischle W, et al. J Biol Chem. ), .
[2] Schuetz A, et al. J Biol Chem. ), .
Trichostatin A (TSA)是一种HDAC抑制剂，无细胞试验中IC50为1.8 nM左右。
Trichostatin A 抑制八种乳腺癌细胞系，包括MCF-7, T-47D, ZR-75-1, BT-474, MDA-MB-231, MDA-MB-453, CAL 51, 和 SK-BR-3增殖，平均IC50为124.4 nM (范围为26.4-308.1 nM),作用于表达ERα的细胞系比作用于表达 ERα阴性的细胞系更有效。Trichostatin A作用于全部乳腺癌细胞系，抑制HDAC活性，平均IC50为 2.4 nM (范围为0.6-2.6 nM), 产生显著的组蛋白 H4高度乙酰化。与 Trapoxin (TPX) 和 Chlamydocin 有效抑制HDAC1 或 HDAC4而不是 HDAC6不同，Trichostatin A 抑制这些HDACs，且抑制程度相似， IC50 分别为6 nM, 38 nM, 和8.6 nM。 Trichostatin A (100 ng/mL) 作用于MIA PaCa-2细胞，通过招募p300和 PCAF进入Sp1-NF-Y HDAC复合体，而诱导转化生长因子βⅡ型受体(TβRII) 表达，复合体与TβRII 启动子的DNA片段结合，伴随着Sp1乙酰化，且与复合体相关的HDAC数理全部降低。
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Administration of Trichostatin A 按 0.5 mg/kg 剂量处理N-甲基-N-亚硝基脲致癌物诱发的大鼠乳腺癌模型，持续处理4周，具有有效的抗癌活性，即使按按高达5 mg/kg剂量处理也没有任何可测量到的毒性。Trichostatin A 按10 mg/kg 剂量单独腹腔注射给药非转基因和脊髓性肌萎缩症（SMA）模型鼠，导致乙酰化的 H3 和 H4组蛋白水平提高，也导致活运动神经元(SMN) 基因表达稍微提高。Trichostatin A 每天按10 mg/kg剂量处理SMA模型鼠，促进存活, 减轻体重下降,且增强运动行为。
推荐的实验操作(此推荐来自于公开的文献所以Selleck并不保证其有效性)
体外HDAC活性
从每种乳腺癌细胞系(MCF-7, T-47D, ZR-75-1, BT-474, MDA-MB-231, MDA-MB-453, CAL 51,或 SK-BR-3)中准备全部细胞提取物。在溶于0.1% (v/v)乙醇的不同浓度Trichostatin A存在时，或者使用0.1% (v/v)乙醇作为对照, 20 μL 细胞粗提取物(~2.5 ×105 个细胞)与 1 μL ~1.5 × 106 cpm
[3H]乙酰标记的组蛋白 H4 肽底物(第2-20位NH2-末端残基) 在25oC下温育60分钟。使用50 μL
1 M HCl/0.16 M 乙酸对每组 200-μL 反应进行淬火，然后使用600 μL 乙酸乙酯进行抽提，通过闪烁计数器测量释放的[3H]乙酸。使用非线性回归曲线拟合抑制数据，绘制合适的剂量反应曲线，而测定IC50。
MCF-7, T-47D, ZR-75-1, BT-474, MDA-MB-231, MDA-MB-453, CAL 51, 和 SK-BR-3
溶于无水酒精,终浓度为~10 μM
使用不同浓度Trichostatin A处理细胞96小时。处理后,使用sulforhodamine B 比色分析测定细胞增殖。通过台酚蓝染色排除法测定细胞活力。
携带NMU诱导的肿瘤的近交系(Ludwig/Wistar/Olac)处女鼠
~5 mg/kg/day
不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）
小鼠大鼠兔豚鼠仓鼠狗
重量 (kg)0.020.151.80.40.0810
体表面积 (m2)0.0070.0250.150.050.020.5
Km 系数36128520
动物A (mg/kg) = 动物B (mg/kg) &&
动物B的Km系数
动物A的Km系数
例如，依据体表面积折算法，将白藜芦醇用于小鼠的剂量22.4 mg/kg 换算成大鼠的剂量，需要将22.4 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到白藜芦醇用于大鼠的等效剂量为11.2 mg/kg。
大鼠剂量 (mg/kg) = 小鼠剂量 (22.4 mg/kg) &&
小鼠的Km系数(3)
&= 11.2 mg/kg
大鼠的Km系数(6)
Clinical Trial Information( data from http://clinicaltrials.gov)
NCT Number
Recruitment
Conditions
Sponsor/Collaborators
Start Date
Recruiting
Fibromyalgia
University Hospital, Brest
October 2015
Recruiting
Glenohumeral Arthritis and/or Rotator Cuff Tear Arthropathy (TSA)|Rotator Cuff Tear (RCR)|Trapeziometacarpal Osteoarthritis (TMC OA)
Matthias Flury|Winterthur Institute of Health Economics (
Matthias Flury|Winterthur Institute of Health Economics (WIG), Switzerland|Schulthess Klinik
November 2013
Active, not recruiting
Massachusetts General Hospital
Osteoarthritis
Columbia University
August 2009
Medasense Biometrics Ltd
November 2008
C17H22N2O3
3年 -20℃粉状
6个月-80℃溶于溶剂
溶解性 (25°C) *
(76.05 mM)
1% DMSO+30% polyethylene glycol+1% Tween 80, pH 4
* &1 mg/ml 指产品微溶或不溶
* 溶解度检测是由Selleck技术部门检测的，可能会和文献中提供的溶解度有所差异，这是由于生产工艺和批次不同产生的正常现象。
Chemical Name
(R,2E,4E)-6-(4-(dimethylamino)benzoyl)-N-hydroxy-4-methylhepta-2,4-dienamide
客户使用Selleck产品的实验数据(4)
Effect of TSA, SAHA and silibinin alone and in combination on left panel: IF staining for p-histone H3 Ser 10 and p-MPM-2 Ser /Thr positive cells and a-tubulin for mitotic spindle and DAPI as nuclear stain in H1299 cells. Right panel: % positive p-histone H3 Ser 10 mitotic cells and expression of p-MPM-2 Ser /Thr protein levels in H1299 cells.
数据来源于
Epigenetics,
7(10):1161-72. Trichostatin A (TSA)购于Selleck
Immunofluorescence staining
H1299 cells
To identify whether these G2/M fractions of cells were arrested at G2 phase or undergoing a mitotic arrest, we analyzed 48 h treated cells for the expression of TSA and Saha, p-histone H3 Ser 10 and p-MPM-2Ser /Thr. As indicated by decreased nuclear expression of p-histone H3 Ser 10, quantitative analysis of immunofluorescence (IF) data showed a significant decrease in mitotic index (% of cells in mitotic phase) by combinatorial treatments. This was further corroborated by decreased expression of MPM-2 reactive structured components of the mitotic apparatus that are required for both onset and completion of M-phase.
HCT116 p53 null cells were treated with different HDACIs (1 &M TSA, 5 &M M344, 1 &M MS-275, 5 mM But, 10 mM VPA) for 24 h, and their expression of GRP78, PERK-eIF2& axis and ATF4, ATF3, CHOP and DR5 proteins.
Biochem Biophys Res Commun,
10.1016/j.bbrc.. Trichostatin A (TSA) purchased from Selleck
Western blot
TSA causes ER stress and increase the expression of ATF4, ATF3, CHOP.
HCT116 p53 null cells were treated with different HDACIs (1 &M TSA, 5 &M M344, 1 &M MS-275, 5 mM But, 10 mM VPA) for 24 h. ATF4, ATF3, CHOP and DR5 proteins were measured by Western blot.
Biochem Biophys Res Commun,
10.1016/j.bbrc.. Trichostatin A (TSA) purchased from Selleck
Western blot
HCT116 p53 null cells
Knockdown of ATF3 suppressed the induction of DR5 protein and knockdown of ATF4 suppressed the induction of ATF3, CHOP and DR5 proteins by these HDACIs(TSA, M344, MS-275).
Western blot analysis of Acetyl-H3 and H3. 0-20&M TSA was added.
Dr. Zhang of Tianjin Medical University. Trichostatin A (TSA) purchased from Selleck
Western blot
MDA-MB-231 cells
Reduction of Histone H3 acetylation in MDA-MB-231 cells treated with Trichostatin A was observed.
客户使用Selleck产品发表的文献(20)
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Vorinostat (SAHA, MK0683)
Vorinostat (suberoylanilide hydroxamic acid, SAHA)是一种HDAC抑制剂，无细胞试验中IC50为~10 nM。
Vorinostat是广谱HDAC活性抑制剂，抑制I和II类酶 。
Entinostat (MS-275)
Entinostat (MS-275)强烈抑制HDAC1和HDAC3，无细胞试验中IC50分别为0.51 μM和1.7 μM，抑制作用强于HDACs 4， 6， 8，和10。Phase 3。
Panobinostat (LBH589)
Panobinostat (LBH589)是一种新型的，广谱HDAC抑制剂，无细胞试验中IC50为5 nM。Phase 3。
Decitabine
Decitabine是一种DNA methylation的有效抑制剂，用于治疗骨髓增生异常综合征(MDS）。
Decitabine 是DNA甲基化的有效抑制剂。
Y-27632 2HCl
Y-27632 2HCl是一种选择性ROCK1(p160ROCK)抑制剂，无细胞试验中Ki为140 nM，比对其他激酶包括PKC，cAMP依赖性蛋白激酶，MLCK和PAK的作用强200多倍。
Romidepsin (FK228, Depsipeptide)
Romidepsin (FK228, Depsipeptide)是一种有效的HDAC1和HDAC2抑制剂，无细胞试验中IC50分别为36 nM和47 nM。
Romidepsin对I型HDAC的抑制作用明显强于对II型HDAC的抑制。
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其他相关的
LMK-235是HDAC4和HDAC5的选择性抑制剂， IC50分别为11.9 nM 和 4.2 nM。
CAY10603是一种强效的选择性HDAC6抑制剂，IC50为2 pM，选择性比其它HDACs高200多倍。
4SC-202是一种选择性的I类HDAC抑制剂，对HDAC1，HDAC2，和HDAC3的IC50分别为1.20 μM，1.12 μM，和0.57 μM。也对Lysine specific demethylase 1 (LSD1)表现出抑制活性。Phase 1。
Panobinostat (LBH589)
Panobinostat (LBH589)是一种新型的，广谱HDAC抑制剂，无细胞试验中IC50为5 nM。Phase 3。
Vorinostat (SAHA, MK0683)
Vorinostat (suberoylanilide hydroxamic acid, SAHA)是一种HDAC抑制剂，无细胞试验中IC50为~10 nM。
Vorinostat是广谱HDAC活性抑制剂，抑制I和II类酶 。
Entinostat (MS-275)
Entinostat (MS-275)强烈抑制HDAC1和HDAC3，无细胞试验中IC50分别为0.51 μM和1.7 μM，抑制作用强于HDACs 4， 6， 8，和10。Phase 3。
Romidepsin (FK228, Depsipeptide)
Romidepsin (FK228, Depsipeptide)是一种有效的HDAC1和HDAC2抑制剂，无细胞试验中IC50分别为36 nM和47 nM。
Romidepsin对I型HDAC的抑制作用明显强于对II型HDAC的抑制。
RGFP966是一种HDAC3抑制剂，无细胞试验中IC50为0.08μM ，比作用于其他HDAC选择性高200倍以上。
Tubastatin A
Tubastatin A是一种有效的，选择性HDAC6抑制剂，无细胞试验中IC50为15 nM，选择性远高于所有其他同工酶(1000倍)除了HDAC8(57倍)。
Mocetinostat (MGCD0103)
Mocetinostat (MGCD0103)是一种有效的HDAC抑制剂，对HDAC1抑制作用最强，无细胞试验中IC50为0.15 μM，比作用于HDAC2， 3，和11选择性高2到10倍，对HDAC4， 5， 6， 7，和8没有抑制活性。Phase 2。
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