Carfilzomib (PR-171) 化学構造
分子量: 719.91

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製品説明

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製品の説明

生物活性

製品説明 Carfilzomib (PR-171) is a proteasome inhibitor with IC50 less than 5 nM.
ターゲット Proteasome
IC50 5 nM [1]
In vitro試験 Carfilzomib inhibits proliferation in a variety of cell lines and patient-derived neoplastic cells, including multiple myeloma, and induced intrinsic and extrinsic apoptotic signaling pathways and activation of c-Jun-N-terminal kinase (JNK). Carfilzomib reveals enhanced anti-MM activity compared with bortezomib, overcome resistance to bortezomib and other agents, and acts synergistically with dexamethasone (Dex). Carfilzomib shoes preferential in vitro inhibitory potency against the ChT-L activity in the β5 subunit, with over 80% inhibition at doses of 10 nM. Short exposure to low-dose Carfilzomib leads to preferential binding specificity for the β5 constitutive 20S proteasome and the β5i immunoproteasome subunits. Measurement of caspase activity in ANBL-6 cells pulsed with Carfilzomib reveals substantial increases in caspase-8, caspase-9, and caspase-3 activity after 8 hours, giving a 3.2-, 3.9- and 6.9-fold increase, respectively, over control cells after 8 hours. In carfilzomib pulse-treated cells, the mitochondrial membrane integrity is decreased to 41% (Q1 + Q2), compared with 75% in vehicle-treated control cells. [1] In another study, Carfilzomib has also shown preclinical effectiveness against hematological and solid malignancies. [2] Carfilzomib directly inhibits osteoclasts formation and bone resorption. [3]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
MM.1S MVzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MVuwMVExOCCwTR?= MWK0PEBp M1KxUGlEPTEEoE5CpFExKG6P MXuyOVMyOjV2Mx?=
NCI-H929  M2K0S2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFjKOJQxNTFyMDDuUS=> M33t[|Q5KGh? M{DFVWlEPTBiPdMgNVQhdk1? NHjxZZgzPTNzMkW0Ny=>
SUDHL16  MnzrRZBweHSxc3nzJGF{e3OjeR?= NF3MflUzNjYkgKOzMlUhdk1? MUi0PEBp NYnN[oFl\W6qYX7j[ZMhfGinIHPlcIwh\GWjdHigZ48ufHKnYYTt[Y51KHerdHigRWN[OTJzNR?= NGr3cWEzPTJ|OUmzOS=>
SUDHL14 MmHJRZBweHSxc3nzJGF{e3OjeR?= Mn36Nk426oDVMz61JI5O NWHEcVJUPDhiaB?= NF\aNlNmdmijbnPld{B1cGViY3XscEBl\WG2aDDjc{11emWjdH3lcpQhf2m2aDDBR3kyOjF3 M3\MdVI2OjN7OUO1
U2932 MYjBdI9xfG:|aYOgRZN{e2G7 NUnrPZNvOi534pETN{42KG6P MXq0PEBp MUPlcohidmOnczD0bIUh[2WubDDk[YF1cCClbz30doVifG2nboSge4l1cCCDQ2mxNlE2 MXuyOVI{QTl|NR?=
P-UMSCC-1 NYPSO|F7T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MoTJTWM2OD1zMT6yJI5O MVKyOFkyPTB|OR?=
R-UMSCC-1 MkLKS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWT6XY5uUUN3ME2yNlk1KG6P NWH5dWRSOjR7MUWwN|k>
P-Cal33 MUPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NV;XTVluUUN3ME2xO{4{KG6P MXuyOFkyPTB|OR?=
R-Cal33 MYTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1i3eGlEPTB;MUGxNkBvVQ>? Mn3kNlQ6OTVyM{m=
Jurkat Mlz2S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MXqxMVEydk1? M4rVblQ5KGh? NXHXfWRRcW6qaXLpeJMhfGinIHPlcIwheHKxbHnm[ZJifGmxbjDjc{11emWjdH3lcpQhf2m2aDD2c5Jqdm:|dHH0 MkPPNlQ5ODFzMki=
Jurkat NF3icnZCeG:ydH;zbZMhSXO|c3H5 MUm4JI5O NF\MU|MzPC92ODDo NFTaNnNqdmS3Y3XzJIFxd3C2b4Ppd{wh[2G|cHHz[UBi[3SrdnH0bY9vNCCjbnSgVGFTWCClbHXheoFo\SClbz30doVifG2nboSge4l1cCC4b4Lpco9{fGG2 M3HlfVI1QDBzMUK4
UMSCC-22A MXPBdI9xfG:|aYOgRZN{e2G7 NE\Vc3czODBibl2= MlrCNlQhcA>? M4fCZolv\HWlZTD0bIUh[2WubDDhdI9xfG:|aYOgZ48ufHKnYYTt[Y51KHerdHigU25ZKDB7MUK= NH\2[oIzOjl{OUiwNy=>
UMSCC-22B NGLy[|JCeG:ydH;zbZMhSXO|c3H5 MlP5NlAxKG6P MWCyOEBp MUnpcoR2[2VidHjlJINmdGxiYYDvdJRwe2m|IHPvMZRz\WG2bXXueEB4cXSqIF;OXEAxQTF{ MV2yNlkzQThyMx?=
1483 MoLkRZBweHSxc3nzJGF{e3OjeR?= MVuyNFAhdk1? MWeyOEBp M{jmcIlv\HWlZTD0bIUh[2WubDDhdI9xfG:|aYOgZ48ufHKnYYTt[Y51KHerdHigU25ZKDB7MUK= NW\yS5l2OjJ7Mkm4NFM>
UMSCC-1 Ml2yRZBweHSxc3nzJGF{e3OjeR?= NFvhZZMzODBibl2= NEGxe3IzPCCq NIDpOZJqdmS3Y3WgeIhmKGOnbHygZZBweHSxc3nzJINwNXS{ZXH0cYVvfCC5aYToJG9PYCByOUGy MlPENlI6Ojl6MEO=
UMSCC-22A NF\qe29Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmnzTWM2OD1|OD63JOKyKDFwMDDuUS=> NVrmSGNIOjJ7Mkm4NFM>
UMSCC-22B NH7QT3NIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NF7WfG9KSzVyPUOwMlchyrFiOT6zJI5O NX;YNXM1OjJ7Mkm4NFM>
1483 M{DnUWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIDHRZVKSzVyPUWwMlUhyrFiMUGuPUBvVQ>? MnjqNlI6Ojl6MEO=
UMSCC-1 MYrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWfRRXQ{UUN3ME2zOE43KMLzIEKuOkBvVQ>? M2nSUFIzQTJ7OECz
Cal33 MXPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYLJR|UxRTR7LkOgxtEhQC57IH7N NXTJeJFWOjJ7Mkm4NFM>
PCI-15A M2nPPWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYKxTZNqUUN3ME23NE41KMLzIEKyMlYhdk1? NYP4SXM1OjJ7Mkm4NFM>
PCI-15B NUPuVGtwT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MULJR|UxRTN7LkWgxtEhOTFwMDDuUS=> M3Lq[FIzQTJ7OECz
OSC-19 MnHpS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{jHT2lEPTB;MUiuN{DDuSB2LkKgcm0> MV2yNlkzQThyMx?=
SUDHL16 MkjIRZBweHSxc3nzJGF{e3OjeR?= NHL1dZEzNjBvND6wJI5O NITO[Fg1QCCq M2HJPYlv\HWlZYOgZ4VtdCCmZXH0bEBkdy22cnXheI1mdnRid3n0bEBw[mG2b3PsZZg> MX[yNlQyOTh7OR?=
SUDHL16 NW\xO|VrTnWwY4Tpc44hSXO|YYm= NFzZdpEzNjVibl2= M3e4dlI1KGh? MoDmZYN1cX[jdHXzJGpPUyxiaX7hZ5RqfmG2ZYOgRWtVNCC3cD3y[Yd2dGG2ZYOgUo95[SxiYX7kJIlv\HWlZYOg{tNJOkFwWDDjc{11emWjdH3lcpQhf2m2aDDvZoF1d2OuYYi= MXOyNlQyOTh7OR?=
Granta MWHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4DYd|AuPCCwTR?= MXW0PEBp MX3pcoR2[2ViY3XscEBl\WG2aDDjc{11emWjdH3lcpQhf2m2aDDIRWREUXN? NHLNW3IzOTd3MEKyOC=>
SUDHL16 M4PQdmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NXzEOHRGOS12IH7N MkfMN|YhcA>? MUHpcoR2[2ViY3XscEBl\WG2aDDjc{11emWjdH3lcpQhf2m2aDDIRWREUXN? MVGyNFI{Ozl5Mx?=

... Click to View More Cell Line Experimental Data

In vivo試験 Carfilzomib moderately reduces tumor growth in an in vivo xenograft model. Carfilzomib effectively decreases multiple myeloma cell viability following continual or transient treatment mimicking. Carfilzomib increases trabecular bone volume, decreases bone resorption and enhances bone formation in non-tumor bearing mice. [3]
臨床試験 Carfilzomib has entered in a Phase II clinical trial in the treatment of multiple myeloma.
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Enzyme-linked immunosorbent assay for subunit profiling of carfilzomib ANBL-6 cells (2 × 106/well) are plated in 96-well plates and treated with Carfilzomib doses from 0.001 to 10 μM for 1 hour. Cells are then lysed (20 mM Tris-HCl, 0.5 mM EDTA), and cleared lysates are transferred to polymerase chain reaction (PCR) plates. A standard curve is generated using untreated ANBL-6 cell lysates starting at a concentration of 6 μg protein/μL. The active site probe [biotin-(CH2)4-Leu-Leu-Leu-epoxyketone; 20 μM] is added and incubated at room temperature for 1 hour. Cell lysates are then denatured by adding 1% sodium dodecyl sulfate (SDS) and heating to 100°C, followed by mixing with 20 μL per well streptavidin-sepharose high-performance beads in a 96-well multiscreen DV plate and incubated for 1 hour. These beads are then washed with enzyme-linked immunosorbent assay (ELISA) buffer (PBS, 1% bovine serum albumin, and 0.1% Tween-20), and incubated overnight at 4°C on a plate shaker with antibodies to proteasome subunits. Antibodies used included mouse monoclonal anti-β1, anti-β2, anti-β1i, and anti-β5i, goat polyclonal anti-β2i, and rabbit polyclonal anti-β5 (affinity-purified antiserum against KLH-CWIRVSSDNVADLHDKYS peptide). The beads are washed and incubated for 2 hours with horseradish peroxidase-conjugated secondary goat antirabbit, goat antimouse or rabbit antigoat antibodies. After washing, the beads are developed using the supersignal ELISA picochemiluminescence substrate. Luminescent detection is performed. Raw luminescence is converted to μg/mL by comparison with the standard curve and expressed as the % inhibition relative to vehicle control. Curve fits are generated using the following nonsigmoidal dose-response equation: Y = Bottom + (Top-Bottom)/(1 + 10̂((LogEC50 − X) × HillSlope)), where X is the logarithm of concentration, Y is the % inhibition, and EC50 is the dose showing 50% effect.

細胞アッセイ: [1]

細胞株 WST-1, ANBL-6 cells
濃度 100 nM
反応時間 1 hour
実験の流れ WST-1 is used to determine the effects of proteasome inhibitor Carfilzomib on cell proliferation. The inhibition of proliferation is calculated in relation to parallel control cells that receives vehicle alone. A linear spline function is used to interpolate the median inhibitory concentration (IC50) using XLfit 4 software. The degree of resistance (DOR) is calculated using the formula: DOR = IC50(resistant cells)/IC50(sensitive cells). ANBL-6 cells pulsed with 100 nM carfilzomib are washed and suspended in PBS containing 5 μg/mL of JC-1, which exhibits potential-dependent accumulation in mitochondria. Analysis of the mitochondrial membrane potential-dependent color shift from 525 to 590 nm is carried out on a FacScan, and the data are analyzed with CellQuest software.

動物実験: [4]

動物モデル Beige-nude-XID mice
製剤 10% sulfobutylether β-cyclodextrin in 10 mmol/L citrate buffer pH 3.5,
投薬量 2.0 mg/kg
投与方法 i.v.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Carfilzomib (PR-171) SDF
分子量 719.91
化学式

C40H57N5O7

CAS No. 868540-17-4
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 50 mg/mL (69.45 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 2% DMSO+castor oil 10mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 L-Phenylalaninamide, (αS)-α-[[2-(4-morpholinyl)acetyl]amino]benzenebutanoyl-L-leucyl-N-[(1S)-3-methyl-1-[[(2R)-2-methyl-2-oxiranyl]carbonyl]butyl]-

カスタマーフィードバック (3)


Click to enlarge
Rating
Source Sci Transl Med, 2014, 6(250), 250ra112. Carfilzomib (PR-171) purchased from Selleck
Method Western blot
Cell Lines Primary myoblasts
Concentrations 5, 10 nM
Incubation Time 24 h
Results To demonstrate that treatment with proteasome inhibitors other than bortezomib can also salvage missense mutated dysferlin, we treated primary myoblasts from patient 2 with either the irreversible proteasome inhibitor carfilzomib, which is the biologically active, hydrolyzed form of the investigational, reversible proteasome inhibitor ixazomib (MLN9708) being developed for oral application. It found that treatment with carfilzomib resulted in a dose-dependent increase in dysferlin expression.

Click to enlarge
Rating
Source Cancer Res, 2014, 74(16), 4458-69. Carfilzomib (PR-171) purchased from Selleck
Method Western blot
Cell Lines MM.1S cells
Concentrations 10 nM
Incubation Time 24 h
Results CHOP expression was induced by carfilzomib indicating ER stress, which was enhanced by TAS-117 and associated with enhanced PARP cleavage.

Click to enlarge
Rating
Source J Virol, 2013, 87(23), 13035-41. Carfilzomib (PR-171) purchased from Selleck
Method Flow cytometry
Cell Lines HeLa cells
Concentrations 1 uM
Incubation Time 24 h
Results The Carfilzomib enhanced the fluorescence of Hela cells, obviously.

文献中の引用 (15)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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