CX-5461

目录号:S2684

CX-5461 Chemical Structure

Molecular Weight(MW): 513.61

CX-5461是一种rRNA synthesis抑制剂,选择性抑制Pol I驱动的rRNA转录,在HCT-116,A375,和 MIA PaCa-2细胞中IC50为142 nM,对Pol II没有作用,对rRNA转录的抑制比对DNA复制和蛋白翻译的抑制选择性高250到300倍。

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客户使用Selleck该产品发表文献18篇:

客户使用该产品的5个实验数据:

  • Pharmacological and siRNA perturbations in HEK293 cells suggest that mTORC1 also modulates cytoplasmic rheology through ribosome crowding in mammals.

    Cell, 2018, 174(2):338-349. CX-5461 purchased from Selleck.

  • The specific Pol I inhibitor CX-5461 causes nucleolar disruption, blocks LTP maintenance and Fsk-induced synthesis of new rRNA. DAPI staining (blue; A, B,C) shows the area of the nucleus. Nomarski images (grey; G, H,I) show the area of the nuclei and nucleoli (arrowheads). Application of Pol I specific inhibitor CX-5461 (200 nM) causes nucleolar disruption as indicated by the distribution of fibrillarin (green); compare A, D to B, E and C, F.

    PLoS One 2014 9(8), e104364. CX-5461 purchased from Selleck.

  • Representative western blot evaluation and densitormetric analysis of p53 expression in control and CX-5461 (CX)-treated HCT116, HepG2, MCF7 and LoVo cells. Cells were exposed to 1 μM CX-5461 for 12 h.

    Oncogene, 2015, 10.1038/onc.2015.147. CX-5461 purchased from Selleck.

  • Cu(CX-5461) exhibits enhanced circulation lifetime of CX-5461 in vivo. When injected intravenously, over 95% of the injected free CX-5461 has left the plasma compartment within an hour (A). When prepared as Cu-CX5461 inside liposomes, about 10% of the drug was still detected via HPLC at 24 h post-injection. Cu(CX-5461) was cleared over a 48 h period as shown (B) and the copper concentration was reduced similarly (C), suggesting that the Cu(CX-5461) complex dissociated and CX-5461 was lost from the lipid vesicles over time. All data are plotted as mean ± SEM.

    J Control Release, 2018, 286:1-9. CX-5461 purchased from Selleck.

  • (B) After CX-5461 treatment at different concentrations for 72 hours, whole cell lysates from OS cells were subjected to Western blot analysis using LC3B-II and actin antibodies. (C) The cells were incubated with 2 mM CX-5461 with or without 2.5 mM 3-MA for 72 hours. The percentage of cell death was determined by CellTiter-Glo™ Luminescent Cell Viability Assay. The data represent the mean of three separate experiments performed in triplicate; bars represent SD. *P<0.05; **P<0.01. +, treatment; −, no treatment. Abbreviations: 3-MA, 3-methyladenine; OS, osteosarcoma; SD, standard deviation.

    Onco Targets Ther, 2016, 9:5985-5997.. CX-5461 purchased from Selleck.

产品安全说明书

DNA/RNA Synthesis抑制剂选择性比较

生物活性

产品描述 CX-5461是一种rRNA synthesis抑制剂,选择性抑制Pol I驱动的rRNA转录,在HCT-116,A375,和 MIA PaCa-2细胞中IC50为142 nM,对Pol II没有作用,对rRNA转录的抑制比对DNA复制和蛋白翻译的抑制选择性高250到300倍。
靶点
Pol I-driven transcription of rRNA [1]
(HCT-116, A375, MIA PaCa-2 cells)
142 nM
体外研究

CX-5461能够选择性抑制HCT-116细胞中rRNA合成(Pol I IC50=142 nM;Pol II IC50 > 25 μM;选择性约200倍)。CX-5461对rRNA合成的选择性抑制在两种其他人类实体肿瘤细胞系,黑色素瘤 A375 (Pol I IC50 = 113 nM;Pol II IC50 > 25 μM)和胰腺癌MIA PaCa-2 (Pol I IC50=54 nM;Pol II IC50 ~25 mM)中得到证实。CX-5461对rRNA转录抑制作用的选择性是对DNA复制和蛋白质翻译的250~300倍。CX-5461对一组人类癌细胞系表现出光谱抗增殖活性,但是对非转化的人类细胞的作用活性很小。所有测试细胞系的中值EC50为147 nM,所有正常细胞系的EC50值大约为5, 000 nM。对HCT-116,A375,和MIA PaCa-2细胞系的抗增殖剂量响应评估的得到的EC50值分别为167,58,和74 nM。CX-5461通过p53-不依赖过程,诱导固体肿瘤细胞自吞噬或衰老,但不诱导细胞凋亡。[1]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MNNG NVO0[phCS2WubDD2bYFjcWyrdImgZZN{[Xl? MU[3NkBp MYDJR|UxRTBwNT2xMlUhyrWP NGn5XoUzPzd{OUiwOy=>
U2-OS M3zDVmNmdGxidnnhZoltcXS7IHHzd4F6 MlL3O|IhcA>? M3LHW2lEPTB;MD61MVEvPSEEtV2= MlHZNlc4Ojl6MEe=
RS4;11 NGfRUXlRem:uaX\ldoF1cW:wIHHzd4F6 Ml\ZNlUxKG6P MV:yOEBp M4ftUZRqdWViZHXw[Y5l\W62IHTlZ5Jm[XOnIHnuJJBzd2yrZnXyZZRqd25icnXsZZRqfmVidH:geIhmcXJiRF3TU{B1emWjdHXkJINwdnS{b3zz MlzRNlY1PzJzMEi=
SEM MYrQdo9tcW[ncnH0bY9vKGG|c3H5 M3;TcVI2OCCwTR?= NEewcmczPCCq NIXpSWl1cW2nIHTldIVv\GWwdDDk[YNz\WG|ZTDpckBxem:uaX\ldoF1cW:wIILlcIF1cX[nIITvJJRp\Wm{IFTNV28hfHKnYYTl[EBkd262cn;sdy=> NUDFR2h[OjZ2N{KxNFg>
KOPN-8 NFjkPINRem:uaX\ldoF1cW:wIHHzd4F6 NHX0cpYzPTBibl2= NUHIUHNxOjRiaB?= M2rOSpRqdWViZHXw[Y5l\W62IHTlZ5Jm[XOnIHnuJJBzd2yrZnXyZZRqd25icnXsZZRqfmVidH:geIhmcXJiRF3TU{B1emWjdHXkJINwdnS{b3zz MkXUNlY1PzJzMEi=
NALM-6 NFXDVlNRem:uaX\ldoF1cW:wIHHzd4F6 NX;W[plkOjVyIH7N MlvmNlQhcA>? NHnHT3N1cW2nIHTldIVv\GWwdDDk[YNz\WG|ZTDpckBxem:uaX\ldoF1cW:wIILlcIF1cX[nIITvJJRp\Wm{IFTNV28hfHKnYYTl[EBkd262cn;sdy=> NImxcFAzPjR5MkGwPC=>

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
Cyclin D1 / p53 / p16; 

PubMed: 29631594     


The cell cycle related proteins cyclin D1, p53, p16 were detected by immunoblotting after treatment with CX-5461 for 48 h, and β-actin was used as loading control.

53BP1 / γ-H2AX / p-ATM; 

PubMed: 29631594     


After treatment for 48 h, CX-5461 induced a strong increase of γ-H2AX, 53BP1, and p-ATM, which are hallmarks of DNA double-strand break response.

Bcl-2 / Bax / Caspase3 ; 

PubMed: 29631594     


The expression of Bcl-2 was significantly decreased, meanwhile the activities of cleaved caspase-3 and Bax were markedly elevated compared with the control group

cleaved PARP / cleaved Caspase-9 / cleaved caspase-3 ; 

PubMed: 28369725     


Immunoblotting of markers of apoptosis including cleaved PARP, caspase-9, and caspase-3 after treatment with 1000 nM CX-5461.

p-AMPK / AMPK / p-mTOR / mTOR; 

PubMed: 27729807     


After OS cells were treated with CX-5461 in a dose-dependent manner for 72 hours, the phosphorylation levels of Akt (Ser473), AMPK (Thr172), mTOR (Ser2448), and their total protein expression were determined by Western blot analysis. 

EG5 / Histone H3 / p-Histone H3 (S10); 

PubMed: 30049386     


Expression of miR-101 target molecules in HCT116 cells after exposure to CX-5461, analyzed by immunoblot analysis at the indicated time points. Concentrations of CX-5461 and incubation times are shown at the top of the image. Data are representative of two independent experiments.

29631594 28369725 27729807 30049386
Immunofluorescence
Vimentin / Phalloidin / Snail1; 

PubMed: 31068593     


Immunostaining of Vimentin (green), Phalloidin (green) and Snail1 (green) ± TGFβ ± CX-5461 in NMuMG cells.

Rictor / Calnexin; 

PubMed: 31068593     


Immunostaining of Rictor (green), Calnexin (red), Rictor/Calnexin (white arrows, yellow) and DAPI (blue) ± TGFβ ± CX-5461 in NMuMG cells.

Fibrillarin; 

PubMed: 25089620     


DAPI staining (blue; A, B,C) shows the area of the nucleus. Nomarski images (grey; G, H,I) show the area of the nuclei and nucleoli (arrowheads). Application of Pol I specific inhibitor CX-5461 (200 nM) causes nucleolar disruption as indicated by the distribution of fibrillarin (green); compare A, D to B, E and C, F.

LC3; 

PubMed: 27729611     


A. U251 cells were transfected with GFP-LC-3 plasmid for 24 h, and then treated with CX-5461 at the indicated concentrations for another 24 h. The cells were imaged under a confocal microscope (scale bar = 10 μm); C. U251 cells were transfected with GFP-LC-3 plasmid for 24 h, and then treated with 250 nM of CX-5461. The cells were imaged under a confocal microscope at the indicated time points post-treatment (scale bar = 10 μm).

γH2AX / 53BP1 / RPA / RAD51; 

PubMed: 28211448     


The formation of γ-H2AX, 53BP1, RPA and RAD51 foci was monitored upon CX-5461, CX-3543 and BMH-21 treatment at 10−7 M in U2OS cells. Drug treatment time is 24 h for all drugs. Scale bar, 10 μM.

chromosome / telomere; 

PubMed: 28211448     


Effect of CX-5461 on telomere fragility in BRCA2+/+ and BRCA2−/−HCT116 cells. Arrows point to telomere defects with either fragile telomeres or missing telomeres. N=3, >100 cells each replica. The data were modelled using a logistic regression model. Scale bar, 5 μM. 

F-actin / Aurora B; 

PubMed: 28369725     


In SKOV3ip1 cells, (C) DAPI (blue) labeling showed failed cytokinesis and an accumulation of multinucleated cells after CX-5461 treatment, with F-actin (red) indicating shared cytoplasm. (D) Aurora-B kinase (red) detection showing normal localization to the cleavage furrow during cytokinesis in control SKOV3ip1 cells. After treatment with CX-5461 Aurora-B mislocalization was apparent in an accumulation of multinucleated cells.

31068593 25089620 27729611 28211448 28369725
Growth inhibition assay
Cell viability; 

PubMed: 26061708     


All eight ALL cell lines showed marked decrease in proliferation after a 3 day treatment with CX-5461.

26061708
体内研究 异种移植人固体肿瘤的小鼠模型中,CX-5461口服生物可利用,且在体内具有抗肿瘤活性。CX-5461显示出显著的MIA PaCa-2 TGI,在第31天,TGI 为69%,与gemcitabine (63% TGI)相当。Gemcitabine是一种阳性对照,其每3天以120 mg/kg腹腔内给药。同样的,CX-5461表现出显著的A375 TGI,第32天的TGI为79%。[1]

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)

激酶实验:[1]
+ 展开

Pol I 和 Pol II 转录活性检测:

两个寿命短暂的RNA转录物(半衰期~20-30 分钟),一个由聚合酶I产生,另一个由聚合酶II产生,通过qRT-PCR定量,作为CX-546对转录的相关作用的测量。45S前体rRNA作为聚合酶I转录物,原癌基因c-myc作为聚合酶II转录物的对比。聚合酶I和聚合酶II转录物均会被通常的细胞应激影响。为最小化应激作用的潜在影响,将细胞在测试试剂下仅暴露很短的时间(2 小时)。如果CX-5461影响它们的合成,暴露的时间足以使这些转录物减少90%以上。
细胞实验:[1]
+ 展开
  • Cell lines: 一组癌细胞和正常细胞系
  • Concentrations: 0-2 μM
  • Incubation Time: 96小时
  • Method: 将细胞接种在96孔板,第二天用剂量响应的CX-5461处理96小时。细胞活性使用Alamar Blue 和CyQUANT试验测定。
    (Only for Reference)
动物实验:[1]
+ 展开
  • Animal Models: 5×106 MIA Paca-2 和 A375 癌细胞皮下注射到5-6周大雌性无胸腺小鼠的右侧面
  • Formulation: CX-5461溶解于50 mM NaH2PO4 (pH 4.5)
  • Dosages: 50 mg/kg
  • Administration: CX-5461通过口服给药,每天一次或每3天一次。
    (Only for Reference)

溶解度 (25°C)

体外 DMF 3 mg/mL warmed (5.84 mM)
DMSO 0.02 mg/mL (0.03 mM)
Water Insoluble

* 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。请按照顺序依次加入各个纯溶剂。

化学数据

分子量 513.61
化学式

C27H27N7O2S

CAS号 1138549-36-6
储存条件 powder
in solvent
别名 N/A

计算器

摩尔浓度计算器

摩尔浓度计算器

本计算器可帮助您计算出特定溶液中溶质的质量、溶液浓度和体积之间的关系,公式为:

质量 (g) = 浓度 (mol/L) x 体积 (L) x 分子量 (g/mol)

摩尔浓度计算公式

  • 质量
    浓度
    体积
    分子量

*在配置溶液时,请务必参考Selleck产品标签上、MSDS / COA(可在Selleck的产品页面获得)批次特异的分子量使用本工具。

稀释计算器

稀释计算器

用本工具协助配置特定浓度的溶液,使用的计算公式为:

开始浓度 x 开始体积 = 最终浓度 x 最终体积

稀释公式

稀释公式一般简略地表示为: C1V1 = C2V2 ( 输入 输出 )

  • C1
    V1
    C2
    V2

在配置溶液时,请务必参考Selleck产品标签上、MSDS / COA(可在Selleck的产品页面获得)批次特异的分子量使用本工具。.

连续稀释计算器方程

  • 连续稀释

  • 计算结果

  • C1=C0/X C1: LOG(C1):
    C2=C1/X C2: LOG(C2):
    C3=C2/X C3: LOG(C3):
    C4=C3/X C4: LOG(C4):
    C5=C4/X C5: LOG(C5):
    C6=C5/X C6: LOG(C6):
    C7=C6/X C7: LOG(C7):
    C8=C7/X C8: LOG(C8):
分子量计算器

分子量计算器

通过输入化合物的化学式来计算其分子量:

总分子量:g/mol

注:化学分子式大小写敏感。C10H16N2O2 c10h16n2o2

摩尔浓度计算器

质量 浓度 体积 分子量
计算

临床试验信息

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02719977 Recruiting Cancer Canadian Cancer Trials Group|Senhwa Biosciences Inc.|Stand Up To Cancer May 16 2016 Phase 1

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操作手册

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  • * 必填项

常见问题及建议解决方法

  • 问题 1:

    I want to make it for further in vivo treatment. I

  • 回答:

    The solubility of this compound is poor in common vehicles. It can be dissolved in DMF at 3 mg/ml with warming.

DNA/RNA Synthesis Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID