Carfilzomib (PR-171)

目录号:S2853

Carfilzomib (PR-171) Chemical Structure

Molecular Weight(MW): 719.91

Carfilzomib (PR-171)是一种不可逆proteasome抑制剂,在ANBL-6细胞中IC50为<5 nM,在体外优先抑制β5亚基的ChT-L活性,对PGPH和T-L活性很弱或没有作用。

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产品安全说明书

Proteasome抑制剂选择性比较

生物活性

产品描述 Carfilzomib (PR-171)是一种不可逆proteasome抑制剂,在ANBL-6细胞中IC50为<5 nM,在体外优先抑制β5亚基的ChT-L活性,对PGPH和T-L活性很弱或没有作用。
靶点
Proteasome [1]
(ANBL-6 cells)
5 nM
体外研究

Carfilzomib抑制多种细胞系和源自患者的肿瘤细胞的增殖,包括多发性骨髓瘤。Carfilzomib诱导内在和外在的凋亡信号传导途径并激活c-Jun N-末端激酶(JNK)。与bortezomib相比,Carfilzomib协同地塞米松(Dex)表现增强的抗MM活性,并克服了bortezomib等药物的抗性。 Carfilzomib有选择地抑制β5亚基的CHT- L活性,在10 nM剂量时抑制超过80%的活性。低剂量Carfilzomib短期处理导致优先结合特异性的β5组成20S蛋白酶体和β5i免疫蛋白酶体亚基。在Carfilzomib刺激的ANBL -6细胞中检测caspase活性,结果显示caspase- 8和caspase -9和caspase-3活性在8小时后大幅增加,和对照8小时后的细胞相比分别增加了3.2 , 3.9和6.9倍。在carfilzomib处理过的细胞中,线粒体膜的完整性减少到41%(Q1 + Q2),而在对照细胞中这一比例为75%。[1] 在另一项研究中,Carfilzomib也表现出对血液和实体肿瘤的临床前有效性。[2] Carfilzomib直接一直破骨形成和骨吸收。[3]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MM.1S MXvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{PKT|AuOTByIH7N NWP3cYFyPDhiaB?= MlqzTWM2OMLiPdMgNVAhdk1? MoHLNlU{OTJ3NEO=
NCI-H929  M2XRXWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVKwMVExOCCwTR?= MXe0PEBp NFfl[GRKSzVyIE5CpFE1KG6P Mkm2NlU{OTJ3NEO=
SUDHL16  MXjBdI9xfG:|aYOgRZN{e2G7 MWiyMlXjiJN|LkWgcm0> MkP5OFghcA>? MYPlcohidmOnczD0bIUh[2WubDDk[YF1cCClbz30doVifG2nboSge4l1cCCDQ2mxNlE2 MnnSNlUzOzl7M{W=
SUDHL14 NVe1WY5USXCxcITvd4l{KEG|c4PhfS=> NUC5dZpUOi534pETN{42KG6P Mln0OFghcA>? MVjlcohidmOnczD0bIUh[2WubDDk[YF1cCClbz30doVifG2nboSge4l1cCCDQ2mxNlE2 NXLyV457OjV{M{m5N|U>
U2932 Mlu0RZBweHSxc3nzJGF{e3OjeR?= NX3s[VExOi534pETN{42KG6P MX[0PEBp M3WzZ4VvcGGwY3XzJJRp\SClZXzsJIRm[XSqIHPvMZRz\WG2bXXueEB4cXSqIFHDXVEzOTV? NWKxUo5lOjV{M{m5N|U>
P-UMSCC-1 M{XxNWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MUjJR|UxRTFzLkKgcm0> M1faNlI1QTF3MEO5
R-UMSCC-1 NFfaTHZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHPzOJRKSzVyPUKyPVQhdk1? NV\OO3A2OjR7MUWwN|k>
P-Cal33 NVvY[JByT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlTRTWM2OD1zNz6zJI5O NIrkd3czPDlzNUCzPS=>
R-Cal33 MXvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3;6S2lEPTB;MUGxNkBvVQ>? NWHOeYZvOjR7MUWwN|k>
Jurkat NFW2d3NIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MkfYNU0yOW6P NG\TeZI1QCCq M{H4ZolvcGmkaYTzJJRp\SClZXzsJJBzd2yrZnXyZZRqd25iY3:teJJm[XSvZX70JJdqfGhidn;ybY5we3SjdB?= NVf0[YhzOjR6MEGxNlg>
Jurkat M{DrN2Fxd3C2b4Ppd{BCe3O|YYm= M33UOFghdk1? NIfaUJYzPC92ODDo NIHo[XFqdmS3Y3XzJIFxd3C2b4Ppd{wh[2G|cHHz[UBi[3SrdnH0bY9vNCCjbnSgVGFTWCClbHXheoFo\SClbz30doVifG2nboSge4l1cCC4b4Lpco9{fGG2 MV6yOFgxOTF{OB?=
UMSCC-22A NVHYZoc4SXCxcITvd4l{KEG|c4PhfS=> NW\odHJQOjByIH7N NXfwSZByOjRiaB?= NIjlZmFqdmS3Y3WgeIhmKGOnbHygZZBweHSxc3nzJINwNXS{ZXH0cYVvfCC5aYToJG9PYCByOUGy M4fjZVIzQTJ7OECz
UMSCC-22B M2[xdmFxd3C2b4Ppd{BCe3O|YYm= MoDuNlAxKG6P NEnB[ZMzPCCq MXXpcoR2[2VidHjlJINmdGxiYYDvdJRwe2m|IHPvMZRz\WG2bXXueEB4cXSqIF;OXEAxQTF{ M3PzN|IzQTJ7OECz
1483 NF:1[m1CeG:ydH;zbZMhSXO|c3H5 M{e4TFIxOCCwTR?= NFzxXmozPCCq MU\pcoR2[2VidHjlJINmdGxiYYDvdJRwe2m|IHPvMZRz\WG2bXXueEB4cXSqIF;OXEAxQTF{ M2D3S|IzQTJ7OECz
UMSCC-1 MmDvRZBweHSxc3nzJGF{e3OjeR?= MkfENlAxKG6P MV[yOEBp M4HHSolv\HWlZTD0bIUh[2WubDDhdI9xfG:|aYOgZ48ufHKnYYTt[Y51KHerdHigU25ZKDB7MUK= NW\VNFdVOjJ7Mkm4NFM>
UMSCC-22A NFvLT4hIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFHxemJKSzVyPUO4MlchyrFiMT6wJI5O MknFNlI6Ojl6MEO=
UMSCC-22B M{\LbWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlXnTWM2OD1|MD63JOKyKDlwMzDuUS=> M2\leFIzQTJ7OECz
1483 NFPqZXlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVvJR|UxRTVyLkWgxtEhOTFwOTDuUS=> MYKyNlkzQThyMx?=
UMSCC-1 M3v1S2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHPyU5FKSzVyPUO0MlYhyrFiMj62JI5O NXHBcllPOjJ7Mkm4NFM>
Cal33 NWDlc3BKT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MU\JR|UxRTR7LkOgxtEhQC57IH7N NHzvUVgzOjl{OUiwNy=>
PCI-15A MX3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NV\WTnpEUUN3ME23NE41KMLzIEKyMlYhdk1? MX:yNlkzQThyMx?=
PCI-15B NIr2c5RIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWfZUY1qUUN3ME2zPU42KMLzIEGxMlAhdk1? MorRNlI6Ojl6MEO=
OSC-19 MUXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NV\H[HhuUUN3ME2xPE4{KMLzIESuNkBvVQ>? MVuyNlkzQThyMx?=
SUDHL16 NVLrd4hQSXCxcITvd4l{KEG|c4PhfS=> M1HkdFIvOC12LkCgcm0> MVK0PEBp NYrO[Zc2cW6mdXPld{Bk\WyuIHTlZZRpKGOxLYTy[YF1dWWwdDD3bZRpKG:kYYTvZ4xigA>? NIrQVGozOjRzMUi5PS=>
SUDHL16 NFXUNJFHfW6ldHnvckBCe3OjeR?= NUnafWNjOi53IH7N NEfrS3gzPCCq NH;6OGVi[3SrdnH0[ZMhUk6NLDDpcoFkfGm4YYTld{BCU1RuIIXwMZJm\3WuYYTld{BPd3ijLDDhcoQhcW6mdXPld{DPu0h{QT7YJINwNXS{ZXH0cYVvfCC5aYToJI9j[XSxY3zhfC=> MnzxNlI1OTF6OUm=
Granta M{TWWmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVqwMVQhdk1? NHnX[VU1QCCq NFLlU3lqdmS3Y3WgZ4VtdCCmZXH0bEBkdy22cnXheI1mdnRid3n0bEBJSUSFSYO= M{i3dVIyPzVyMkK0
SUDHL16 M{\ve2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnvONU01KG6P MoThN|YhcA>? NX;1OoZOcW6mdXPlJINmdGxiZHXheIgh[29vdILlZZRu\W62IIfpeIghUEGGQ1nz MV2yNFI{Ozl5Mx?=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
pERK / ERK / pSTAT5 / STAT5 / pPI3K / PI3K; 

PubMed: 24590311     


Western blot analysis for activated (phosphorylated) ERK, Stat5 and PI3K signaling pathways following exposure to carfilzomib, total levels of ERK, Stat5 and PI3K were used as a loading control.

caspase-9 / caspase-8; 

PubMed: 24590311     


Western blot analysis for activated (cleaved) caspase-8 and caspase-9 following exposure to carfilzomib.

c-PARP / PARP / caspase-3; 

PubMed: 22929803     


UMSCC-22A, UMSCC-22B, 1483 and UMSCC-1 cells were treated for 24 hours with 0.1% DMSO, or 200 nmol/L carfilzomib or ONX 0912, followed by immunoblotting with anti-PARP, anti-caspase-3, or anti-β-actin. Shown are full-length PARP, cleaved PARP (c-PARP), and the cleaved, active subunits of caspase-3. Similar results were obtained in 3 independent experiments.

Bcl-2 / Bcl-Xl / Mcl-1 / Bik / Bim / Bax / Bak; 

PubMed: 22929803     


UMSCC-22A, UMSCC-22B, 1483 and UMSCC-1 cells were treated for 24 hours with 0.1% DMSO, or 100 nmol/L carfilzomib or ONX 0912, followed by immunoblotting for the indicated proteins. In the case of Bik immunoblotting, cells were treated with 200 nmol/L carfilzomib or ONX 0912 to more clearly demonstrate Bik upregulation in 1483 and UMSCC-1 cells. Blots shown are representative of 3 independent experiments. 

Atg5 / Atg12 / Beclin-1 / LC3-II; 

PubMed: 22929803     


HNSCC cells were treated for 24 hours with 100 nmol/L carfilzomib or ONX 0912, or with 0.1% DMSO. Immunoblots were probed for Beclin-1, Atg5/12 conjugate, LC3-II, or β-actin. Representative blots from 3 independent experiments are shown. 

Noxa / Bik / Puma / Mcl-1; 

PubMed: 25548100     


SW620 cells were treated with the indicated dosage for 48 h. Expression of Noxa, Bik and/or Puma, c-myc and Mcl-1 proteins was then analyzed by immunoblotting. Tubulin served as control for protein loading. 

EGFR / HER2 / ER alpha / p-Akt(Ser473) / Akt / p-ERK / ERK / p53; 

PubMed: 29069787     


T47D and MCF7 cells were cultured with the indicated carfilzomib concentrations for 32 or 36 hours, respectively. Western blots of protein lysates were probed with the indicated antibodies. β-actin served as loading control.

BDP1 / HER2(Tyr1248) / HER2(Tyr1221/Tyr1222) / PARP1 / caspase-7 / p53 Mut; 

PubMed: 29069787     


BT474 cells were cultured in the presence of the indicated carfilzomib concentrations for 32 hours. Western blots of protein lysates were probed with the indicated antibodies.

HLA class I; 

PubMed: 26323098     


Immunofluorescence analysis was performed to confirm the consequence that down-regulation of HLA class I was in a dose- and time-dependent manner.

24590311 22929803 25548100 29069787 26323098
Growth inhibition assay
Cell viability; 

PubMed: 27655642     


Cytotoxic effects of carfilzomib on breast cancer cells in MTT assays. Seven human breast cancer cell lines, MCF7, T-47D, MDA-MB-361, HCC1954, MDA-MB-468, MDA-MB-231, and BT-549 were treated with carfilzomib at 0, 0.001 μM, 0.01 μM, 0.05 μM, 0.1 μM, 1 μM, 10 μM, or 50 μM for 72 h, then subjected to MTT assays. The absorbance of each well was measured at 540 nm and plotted for the cell viability curve. IC50 values of carfilzomib in breast cancer cell lines were listed.

27655642
体内研究 Carfilzomib适度降低了体内异种移植物模型中肿瘤的生长。在持续或短暂处理下, Carfilzomib有效地降低多发性骨髓瘤细胞活力。 Carfilzomib增加骨小梁体积,减少骨吸收,并提高非肿瘤小鼠的骨形成。[3]

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

酶联免疫吸附试验分析carfilzomib亚基:

ANBL -6细胞(2 ×106/孔)接种于96孔板中并用Carfilzomib(0.001至10μM)处理 1小时。然后将细胞裂解(20mM的Tris-HCl, 0.5 mM EDTA),并裂解物上清转移到聚合酶链反应(PCR)平板上。使用起始浓度为6 μg/μL处理ANBL - 6细胞得到的裂解物做标准曲线。活性位点探针[生物素-(CH2)4-Leu-Leu-Leu-环氧酮; 20 μM]加入并于室温温育1小时。在细胞裂解液中添加1%十二烷基硫酸钠(SDS)和加热至100℃变性 ,随后在96孔的多屏DV板中每孔和20μL链霉亲和琼脂糖高性能珠混合并孵育1小时。这些珠粒用酶联免疫吸附试验(ELISA)缓冲液(PBS,1%牛血清白蛋白和0.1 %吐温-20)洗涤细胞,并温育过夜,在4℃在板振荡器上与抗体的蛋白酶体亚基反应。所用抗体包括鼠单克隆抗- β1 ,抗-β2 ,抗β1i和抗β5i ,山羊多克隆抗β2i ,和兔多克隆抗- β5 (针对KLH- CWIRVSSDNVADLHDKYS肽亲和纯化的抗血清)。珠粒洗涤后用以辣根过氧化物酶标记的二羊抗兔,羊抗鼠或兔antigoat抗体温育2小时。洗涤后,将珠粒用SuperSignal ELISA picochemiluminescence底物反应,而后进行荧光检测。荧光信号通过与标准曲线比较转换为μg/mL,表示为抑制相对于对照的%。使用以下nonsigmoidal剂量 - 反应方程生成拟合曲线:Y = Bottom + (Top-Bottom)/(1 + 10̂((LogEC50 − X) × HillSlope)),其中X是浓度的对数, Y是抑制%,EC 50是表示50%的效果的剂量。
细胞实验:[1]
+ 展开
  • Cell lines: WST-1, ANBL-6细胞
  • Concentrations: 100 nM
  • Incubation Time: 1小时
  • Method: WST-1被用于确定蛋白酶体抑制剂Carfilzomib对细胞增殖的影响。增殖的抑制作用是与对照细胞比较所得。线性样条函数是用来使用XLfit4软件进行计算半数抑制浓度(IC50)。抗性程度(DOR)的计算公式是IC50(抗性细胞)/ IC50(敏感细胞)。 ANBL-6细胞用100nM carfilzomib短暂处理,洗涤并悬浮于含有5μg/mL JC-1PBS中,它显示出在线粒体电位依赖性积聚。用FACScan分析线粒体膜电位依赖性颜色转变(从525到590 nM),数据用CellQuest软件分析。
    (Only for Reference)
动物实验:[4]
+ 展开
  • Animal Models: Beige-nude-XID小鼠
  • Formulation: 10%sulfobutylether β-cyclodextrin 在10 mmol / L的柠檬酸盐缓冲液(pH3.5)中
  • Dosages: 2.0 mg/kg
  • Administration: 静脉注射
    (Only for Reference)

溶解度 (25°C)

体外 DMSO 50 mg/mL (69.45 mM)
Water Insoluble
Ethanol Insoluble
体内 从左到右依次将纯溶剂加入产品,现配现用(数据来自Selleck实验检测而非文献):
2% DMSO+30% PEG 300+2%Tween 80+ddH2O
1mg/mL

* 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 719.91
化学式

C40H57N5O7

CAS号 868540-17-4
稳定性 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
NCT03795597 Not yet recruiting Multiple Myeloma Loyola University|Amgen February 1 2020 Phase 1|Phase 2
NCT03795597 Not yet recruiting Multiple Myeloma Loyola University|Amgen February 1 2020 Phase 1|Phase 2
NCT03871829 Not yet recruiting Multiple Myeloma Janssen Research & Development LLC May 31 2019 Phase 2
NCT03871829 Not yet recruiting Multiple Myeloma Janssen Research & Development LLC May 31 2019 Phase 2
NCT03859427 Not yet recruiting Relapsed or Refractory Multiple Myeloma Amgen April 23 2019 Phase 3
NCT03859427 Not yet recruiting Relapsed or Refractory Multiple Myeloma Amgen April 23 2019 Phase 3

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操作手册

如果有其他问题,请给我们留言。

  • * 必填项

常见问题及建议解决方法

  • 问题 1:

    How should I prepare solution of Carfilzomib for ongoing in vivo study?

  • 回答:

    This compound can be dissolved in 2% DMSO/30% PEG 300/dd H2O at 10 mg/ml as a suspension, and can be dissolved in 2% DMSO/ castor oil at 10 mg/ml as a clear solution.

Proteasome Signaling Pathway Map

Proteasome Inhibitors with Unique Features

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID