Quisinostat (JNJ-26481585) 2HCl

Quisinostat (JNJ-26481585) 2HCl是一种新型的,第二代HDAC抑制剂,对HDAC1最有效,无细胞试验中IC50为0.11 nM,作用于HDACs 2,4,10,和11适度有效;比作用于HDACs 3,5,8,和9选择性强30倍,对HDACs 6和7作用效果最弱。Phase 2。

Quisinostat (JNJ-26481585) 2HCl Chemical Structure

Quisinostat (JNJ-26481585) 2HCl Chemical Structure

CAS: 875320-31-3

规格 价格 库存 购买数量
10mM (1mL in DMSO) 2691.01 现货
5mg 1726.45 现货
50mg 7921.36 现货
1g 67731.3 现货
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Quisinostat (JNJ-26481585) 2HCl相关产品

相关信号通路图

细胞实验数据示例

细胞系 实验类型 给药浓度 孵育时间 活性描述 文献信息
HepG2 Cell viability assay 5, 10, 20, 40, 80, 160 and 320 nM 24, 48, 72 h The IC50 values of cells for quisinostat treatment at 48 and 72 h were 81.2 and 30.8 nM, respectively. 28849080
RD cells Function assay 15 nM 24 h and 30 h GSK690 and JNJ-26481585 cooperated to induce cleavage of the initiator caspase-9 into its active p35 and p37 fragments and of the effector caspase-3 into its active p12 and p17 fragments 28617441
RH30 cells Function assay 15 nM 24 h and 30 h GSK690 and JNJ-26481585 cooperated to induce cleavage of the initiator caspase-9 into its active p35 and p37 fragments and of the effector caspase-3 into its active p12 and p17 fragments 28617441
HuT78 Function assay 10 nM increases the level of acetylated lysine K10 of histone H3 30012418
A549 cells Cell viability assay 24, 48, or 72 h the IC50 values of cells for 48 and 72 h of quisinostat treatment were 82.4 and 42.0 nM, respectively. 27423454
HUT78 Function assay 18 hrs Pro-apoptotic activity in human HUT78 cells after 18 hrs by caspase-Glo 3/7 assay, EC50 = 0.0065 μM. 30122227
Sf9 Function assay Inhibition of full length recombinant human HDAC1 expressed in baculovirus infected Sf9 cells using RHKK-Ac as substrate by fluorescence analysis, IC50 = 0.00011 μM. 27606546
Sf9 Function assay Inhibition of full length recombinant human HDAC2 expressed in baculovirus infected Sf9 cells using RHKK-Ac as substrate by fluorescence analysis, IC50 = 0.00033 μM. 27606546
Sf9 Function assay Inhibition of full length recombinant human HDAC3/NCOR2 expressed in baculovirus infected Sf9 cells using RHKK-Ac as substrate by fluorescence analysis, IC50 = 0.00486 μM. 27606546
BL21 (DE3) Function assay Binding affinity to human His-thioredoxin-tagged HDAC8 expressed in Escherichia coli BL21 (DE3) cells by ITC method, Kd = 0.0227 μM. 30347148
BL21 (DE3) Function assay Binding affinity to Schistosoma mansoni His-tagged HDAC8 expressed in Escherichia coli BL21 (DE3) cells by ITC method, Kd = 0.0284 μM. 30347148
BL21 (DE3) Function assay Inhibition of human His-thioredoxin-tagged HDAC8 expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method, IC50 = 0.0644 μM. 30347148
Sf9 Function assay Inhibition of full length recombinant human HDAC6 expressed in baculovirus infected Sf9 cells using RHKK-Ac as substrate by fluorescence analysis, IC50 = 0.0768 μM. 27606546
BL21 (DE3) Function assay Inhibition of human His-thioredoxin-tagged HDAC8 mL6 mutant expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method, IC50 = 0.093 μM. 30347148
BL21 (DE3) Function assay Inhibition of human His-thioredoxin-tagged HDAC8 mL1/mL6 mutant expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method, IC50 = 0.094 μM. 30347148
BL21 (DE3) Function assay Inhibition of human His-thioredoxin-tagged HDAC8 mL6/L179I mutant expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method, IC50 = 0.169 μM. 30347148
BL21 (DE3) Function assay Inhibition of human His-thioredoxin-tagged HDAC8 mL1/mL6/L179I mutant expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method, IC50 = 0.217 μM. 30347148
BL21 (DE3) Function assay Inhibition of Schistosoma mansoni His-tagged HDAC8 expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method, IC50 = 0.3034 μM. 30347148
TC32 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells 29435139
U-2 OS qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells 29435139
A673 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells 29435139
DAOY qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells 29435139
Saos-2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells 29435139
BT-37 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells 29435139
RD qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells 29435139
SK-N-SH qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells 29435139
BT-12 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells 29435139
MG 63 (6-TG R) qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells 29435139
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells 29435139
OHS-50 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells 29435139
BT-12 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-12 cells 29435139
DAOY qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for DAOY cells 29435139
fibroblast cells qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for control Hh wild type fibroblast cells 29435139
SK-N-SH qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-SH cells 29435139
Rh41 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells 29435139
A673 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for A673 cells) 29435139
Rh30 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh30 cells 29435139
MG 63 (6-TG R) qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for MG 63 (6-TG R) cells 29435139
fibroblast cells qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for control Hh wild type fibroblast cells 29435139
Rh30 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh30 cells 29435139
U-2 OS qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for U-2 OS cells 29435139
OHS-50 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for OHS-50 cells 29435139
SK-N-SH qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for SK-N-SH cells 29435139
Rh41 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh41 cells 29435139
RD qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for RD cells 29435139
Daoy qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for Daoy cells 29435139
TC32 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for TC32 cells 29435139
MG 63 (6-TG R) qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for MG 63 (6-TG R) cells 29435139
SJ-GBM2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells 29435139
SK-N-MC qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells 29435139
NB-EBc1 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells 29435139
LAN-5 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells 29435139
Rh18 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells 29435139
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for NB1643 cells 29435139
SJ-GBM2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SJ-GBM2 cells 29435139
Rh18 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh18 cells 29435139
Saos-2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Saos-2 cells 29435139
SJ-GBM2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for SJ-GBM2 cells 29435139
RD qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for RD cells 29435139
点击查看更多细胞系数据

生物活性

产品描述 Quisinostat (JNJ-26481585) 2HCl是一种新型的,第二代HDAC抑制剂,对HDAC1最有效,无细胞试验中IC50为0.11 nM,作用于HDACs 2,4,10,和11适度有效;比作用于HDACs 3,5,8,和9选择性强30倍,对HDACs 6和7作用效果最弱。Phase 2。
特性 JNJ-26481585是口服生物有效性的,二代氧肟酸基的HDAC抑制剂。
靶点
HDAC1 [1]
(Cell-free assay)
HDAC2 [1]
(Cell-free assay)
HDAC11 [1]
(Cell-free assay)
HDAC10 [1]
(Cell-free assay)
HDAC4 [1]
(Cell-free assay)
点击更多
0.11 nM 0.33 nM 0.37 nM 0.46 nM 0.64 nM
体外研究(In Vitro)
体外研究活性

体外, JNJ-26481585有效抑制一组重组HDAC酶,最有效抑制HDAC1,IC50为 0.11 nM,另外抑制其他家族成员如HDAC2, 4, 10和 11时效果稍微低点,IC50分别为0.33 nM, 0.64 nM, 0.46 nM 和0.37 nM。[1] JNJ-26481585 作用于实体瘤和血癌细胞系,如肺癌,乳腺癌,结肠癌,前列腺癌,脑癌,和卵巢癌细胞系,IC50 为3.1 到 246 nM,具有广谱抗增殖活性,作用于多种人类癌细胞系时,JNJ-26481585效果比 R306465, CRA-24781, 和 Mocetinostat 好。[1] 最新研究显示JNJ-26481585 在低纳摩尔浓度时通过耗尽Mcl-1及诱导Hsp72产生而促进骨髓癌细胞死亡。[2]

激酶实验 HDAC 活性实验
使用杆状病毒感染的Sf9细胞表达全长HDAC蛋白。此外, HDAC3共表达作为与人类NCOR2作用的复合体。为了测定含HDAC1细胞复合体活性, 免疫沉淀反应的HDAC1复合体和组蛋白H4肽段[生物素-(6-氨基)Gly-Ala-(乙酰基[3H])Lys-Arg-His-Arg-Lys-Val-NH2]的[3H]乙酰基标记的片段在50μL酶实验buffer(25mM HEPES (pH 7.4),1 M 蔗糖, 0.1 mg/mL BSA 和0.01% (v/v) Triton X-100)中温育。在37oC下温育45分钟,或者在室温下温育30分钟。加入底物之前,加入浓度不断增加的HDAC抑制剂,然后在室温下预温育10分钟。温育后,加入35μL 终止 buffer (1 M HCl 和0.4 M 乙酸)终止反应。用800μL乙酸乙酯提取释放 [3H]乙酸,然后通过闪烁计数器量化。通过Western blot 分析,测定等量的进行免疫沉淀反应的HDAC1。
细胞实验 细胞系 NCL-H2106, Colo699和 LNCAP
浓度 0到300 nM
孵育时间 24 小时
方法

使用MTT测定HDAC抑制剂抑制细胞增殖的效果。使用Alamar Blue法测定非小细胞肺癌(NSCLC)细胞系的增殖。为了测定 血癌细胞系的增殖,细胞温育72小时,通过 MTS实验测评毒性。进行三次平行实验,测定 IC50。

实验图片 检测方法 检测指标 实验图片 PMID
Western blot HDAC1 / HDAC2 / HDAC4 p21 / CDK2 / CDK4 / CDK6 / Cyclin D1 / Cyclin E1 / Cyclin A2 Caspase-3/ Cleaved caspase-3 / caspase-9 / Cleaved caspase-9 / PARP / Cleaved PARP / Bcl-xl / Bcl2 / Bax / Survivin PI3K-p110 / PI3K-p85 / p-AKT / JNK / p-JNK / p-c-Jun 30443188
Growth inhibition assay Cell viability 30443188
体内研究(In Vivo)
体内研究活性

JNJ-26481585按最大耐受剂量(10 mg/kg腹腔注射及40 mg/kg口服处理)作用于对HDAC1敏感的A2780卵巢癌模型3天,导致产生HDAC1-调节的荧光, 可测的抑制肿瘤生长效果。JNJ-26481585更有效抑制C170HM2大肠癌肝转移。[1]

动物实验 Animal Models 在腹股沟区皮下注射HCT116人类结肠癌细胞的雄性NMRI nu/nu无胸腺鼠, 腹腔注射溶于1 mL 0.9% NaCl(pH 7.3)的C170HM2细胞悬浮液的雄性MFI裸鼠
Dosages ≤10 mg/kg
Administration 口服处理或腹腔注射
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02948075 Completed
Ovarian Cancer
NewVac LLC|Janssen Pharmaceutica N.V. Belgium
September 2015 Phase 2
NCT01464112 Completed
Multiple Myeloma
Janssen Research & Development LLC
September 16 2011 Phase 1
NCT00676728 Terminated
Advanced or Refractory Leukemia|Myelodysplastic Syndromes
Johnson & Johnson Pharmaceutical Research & Development L.L.C.
December 2008 Phase 1
NCT00677105 Completed
Lymphoma|Neoplasms
Johnson & Johnson Pharmaceutical Research & Development L.L.C.|Janssen Pharmaceutica N.V. Belgium
August 2007 Phase 1

化学信息&溶解度

分子量 467.39 分子式

C21H28Cl2N6O2

CAS号 875320-31-3 SDF --
Smiles CN1C=C(C2=CC=CC=C21)CNCC3CCN(CC3)C4=NC=C(C=N4)C(=O)NO.Cl.Cl
储存条件(自收到货起)

体外溶解度
批次:

DMSO : 79 mg/mL ( (169.02 mM) ;DMSO吸湿会降低化合物溶解度,请使用新开封DMSO)

Water : Insoluble

Ethanol : Insoluble

摩尔浓度计算器

体内溶解度
批次:

现配现用,请按从左到右的顺序依次添加,澄清后再加入下一溶剂

动物体内配方计算器

实验计算

摩尔浓度计算器

质量 浓度 体积 分子量

动物体内配方计算器(澄清溶液)

第一步:请输入基本实验信息(考虑到实验过程中的损耗,建议多配一只动物的药量)

mg/kg g μL

第二步:请输入动物体内配方组成(配方适用于不溶于水的药物;不同批次药物配方比例不同,请联系Selleck为您提供正确的澄清溶液配方)

% DMSO % % Tween 80 % ddH2O
%DMSO %

计算结果:

工作液浓度: mg/ml;

DMSO母液配制方法: mg 药物溶于μL DMSO溶液(母液浓度mg/mL,:如该浓度超过该批次药物DMSO溶解度,请先联系Selleck);

体内配方配制方法:μL DMSO母液,加入μL PEG300,混匀澄清后加入μL Tween 80,混匀澄清后加入μL ddH2O,混匀澄清。

体内配方配制方法:μL DMSO母液,加入μL Corn oil,混匀澄清。

注意:1. 首先保证母液是澄清的;
2.一定要按照顺序依次将溶剂加入,进行下一步操作之前必须保证上一步操作得到的是澄清的溶液,可采用涡旋、超声或水浴加热等物理方法助溶。

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常见问题及建议解决方法

问题 1:
I was thinking of resuspending the powder in 10% hydroxy-propyl-β-cyclodextrin, 25mg/ml mannitol, in sterile water (final pH 8.7). Is this a good vehicle to use? What is the solubility of this chemical in such a vehicle?

回答:
This vehicle can be used for in vivo studies. The following papers also used this vehicle: 1. http://www.nature.com/leu/journal/v23/n10/full/leu2009121a.html; 2. http://cancerres.aacrjournals.org/content/69/13/5307.long (The solvent contains 10% hydroxypropyl-β-cyclodextrin, 0.8% HCl (0.1 N), 0.9 % NaOH (0.1 N), 3.4% mannitol and pyrogen-free water). The solubility is 2mg/ml.

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