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 M4O2c2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MUSwMVExOCCwTR?= MlvIOFghcA>? MU\JR|UxyqB;wrCxNEBvVQ>? MU[yOVMyOjV2Mx?=
NCI-H929  NXPkRm06T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXGwMVExOCCwTR?= MXK0PEBp MmnsTWM2OCB;wrCxOEBvVQ>? M1;qUVI2OzF{NUSz
SUDHL16  MlnRRZBweHSxc3nzJGF{e3OjeR?= MlvSNk426oDVMz61JI5O M37F[lQ5KGh? MXLlcohidmOnczD0bIUh[2WubDDk[YF1cCClbz30doVifG2nboSge4l1cCCDQ2mxNlE2 MWSyOVI{QTl|NR?=
SUDHL14 NG\NbpFCeG:ydH;zbZMhSXO|c3H5 MnfiNk426oDVMz61JI5O M3PBVlQ5KGh? MV3lcohidmOnczD0bIUh[2WubDDk[YF1cCClbz30doVifG2nboSge4l1cCCDQ2mxNlE2 MlvnNlUzOzl7M{W=
U2932 M{nW[mFxd3C2b4Ppd{BCe3O|YYm= MY[yMlXjiJN|LkWgcm0> MV60PEBp NVXGdYNs\W6qYX7j[ZMhfGinIHPlcIwh\GWjdHigZ48ufHKnYYTt[Y51KHerdHigRWN[OTJzNR?= M375cFI2OjN7OUO1
P-UMSCC-1 Mo[zS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MkDHTWM2OD1zMT6yJI5O NIPBfYYzPDlzNUCzPS=>
R-UMSCC-1 Mke5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MoDzTWM2OD1{Mkm0JI5O NIT2[4kzPDlzNUCzPS=>
P-Cal33 M{TwXGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MWjJR|UxRTF5LkOgcm0> Mo\vNlQ6OTVyM{m=
R-Cal33 M3TyeGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUDnb4ozUUN3ME2xNVEzKG6P NWT0Z4d2OjR7MUWwN|k>
Jurkat M3HjTmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIrtcIQyNTFzbl2= M3nDVVQ5KGh? NUjZN5pMcW6qaXLpeJMhfGinIHPlcIwheHKxbHnm[ZJifGmxbjDjc{11emWjdH3lcpQhf2m2aDD2c5Jqdm:|dHH0 NXLPeHg3OjR6MEGxNlg>
Jurkat M1XGWWFxd3C2b4Ppd{BCe3O|YYm= NYLaW4FvQCCwTR?= NVfhd49EOjRxNEigbC=> NXLRdnA4cW6mdXPld{BieG:ydH;zbZMtKGOjc4Dhd4Uh[WO2aY\heIlwdixiYX7kJHBCWlBiY3zlZZZi\2ViY3:teJJm[XSvZX70JJdqfGhidn;ybY5we3SjdB?= NEG2[pkzPDhyMUGyPC=>
UMSCC-22A MnWyRZBweHSxc3nzJGF{e3OjeR?= NES3RWMzODBibl2= MlXxNlQhcA>? NIHtUZZqdmS3Y3WgeIhmKGOnbHygZZBweHSxc3nzJINwNXS{ZXH0cYVvfCC5aYToJG9PYCByOUGy MX2yNlkzQThyMx?=
UMSCC-22B NInnWo9CeG:ydH;zbZMhSXO|c3H5 M{HPR|IxOCCwTR?= MnHoNlQhcA>? MnjJbY5lfWOnIITo[UBk\WyuIHHwc5B1d3OrczDjc{11emWjdH3lcpQhf2m2aDDPUnghODlzMh?= NFHRO5gzOjl{OUiwNy=>
1483 MmLERZBweHSxc3nzJGF{e3OjeR?= MorWNlAxKG6P NYD3WYhyOjRiaB?= M3LOW4lv\HWlZTD0bIUh[2WubDDhdI9xfG:|aYOgZ48ufHKnYYTt[Y51KHerdHigU25ZKDB7MUK= MWOyNlkzQThyMx?=
UMSCC-1 MX;BdI9xfG:|aYOgRZN{e2G7 M2Hk[|IxOCCwTR?= M3nvSlI1KGh? NG\lUGNqdmS3Y3WgeIhmKGOnbHygZZBweHSxc3nzJINwNXS{ZXH0cYVvfCC5aYToJG9PYCByOUGy NEfxT3MzOjl{OUiwNy=>
UMSCC-22A NYf6ZpdoT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUjlXVdiUUN3ME2zPE44KMLzIEGuNEBvVQ>? NHjkXlMzOjl{OUiwNy=>
UMSCC-22B M4rNZmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2nCTmlEPTB;M{CuO{DDuSB7LkOgcm0> MoeyNlI6Ojl6MEO=
1483 NIXuPINIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2e3TmlEPTB;NUCuOUDDuSBzMT65JI5O M4TMZlIzQTJ7OECz
UMSCC-1 MlH1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHrzOodKSzVyPUO0MlYhyrFiMj62JI5O M4\LVlIzQTJ7OECz
Cal33 NH;TZ4RIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2\YTmlEPTB;NEmuN{DDuSB6Lkmgcm0> NVfnSGdPOjJ7Mkm4NFM>
PCI-15A M4\UUmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MV3JR|UxRTdyLkSgxtEhOjJwNjDuUS=> M{e4XFIzQTJ7OECz
PCI-15B MXHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MmjJTWM2OD1|OT61JOKyKDFzLkCgcm0> NYP4V4xqOjJ7Mkm4NFM>
OSC-19 MVrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVXwbHB[UUN3ME2xPE4{KMLzIESuNkBvVQ>? MYqyNlkzQThyMx?=
SUDHL16 NH65OnJCeG:ydH;zbZMhSXO|c3H5 M2LkXFIvOC12LkCgcm0> M3L6VlQ5KGh? NEPwc4JqdmS3Y3XzJINmdGxiZHXheIgh[29vdILlZZRu\W62IIfpeIghd2KjdH;jcIF5 M3TxVVIzPDFzOEm5
SUDHL16 M3vhNWZ2dmO2aX;uJGF{e2G7 MVeyMlUhdk1? M4LEW|I1KGh? M1K5fIFkfGm4YYTld{BLVktuIHnuZYN1cX[jdHXzJGFMXCxidYCtdoVofWyjdHXzJG5wgGFuIHHu[EBqdmS3Y3XzJO6{UDKDLmigZ48ufHKnYYTt[Y51KHerdHigc4JifG:lbHH4 MkGwNlI1OTF6OUm=
Granta NYHIRo1mT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmiwNE01KG6P M3LwWVQ5KGh? MnKybY5lfWOnIHPlcIwh\GWjdHigZ48ufHKnYYTt[Y51KHerdHigTGFFS0m| M4DuUlIyPzVyMkK0
SUDHL16 NV;Vb5B3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NY\0O|dKOS12IH7N MVqzOkBp NYjlemcycW6mdXPlJINmdGxiZHXheIgh[29vdILlZZRu\W62IIfpeIghUEGGQ1nz MU[yNFI{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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