Carfilzomib (PR-171)

Catalog No.S2853

Carfilzomib (PR-171) is an irreversible proteasome inhibitor with IC50 of <5 nM in ANBL-6 cells, displayed preferential in vitro inhibitory potency against the ChT-L activity in the β5 subunit, but little or no effect on the PGPH and T-L activities.

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Carfilzomib (PR-171) Chemical Structure

Carfilzomib (PR-171) Chemical Structure
Molecular Weight: 719.91

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Product Description

Biological Activity

Description Carfilzomib (PR-171) is an irreversible proteasome inhibitor with IC50 of <5 nM in ANBL-6 cells, displayed preferential in vitro inhibitory potency against the ChT-L activity in the β5 subunit, but little or no effect on the PGPH and T-L activities.
Targets Proteasome [1]
(ANBL-6 cells)
IC50 5 nM
In vitro 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.1SNYezN4VxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=MnPnNE0yODBibl2=NWLRV5VvPDhiaB?=NYDNSYc3UUN3MNMgQeKhOTBibl2=MlTJNlU{OTJ3NEO=
NCI-H929 NW\WUmxHT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M3Ti[lAuOTByIH7NNVjB[2dMPDhiaB?=M3HGSWlEPTBiPdMgNVQhdk1?NFTtfnEzPTNzMkW0Ny=>
SUDHL16 NIPQcpNCeG:ydH;zbZMhSXO|c3H5NXzGUWlyOi534pETN{42KG6PNFW5UmQ1QCCqMkG2[Y5p[W6lZYOgeIhmKGOnbHyg[IVifGhiY3:teJJm[XSvZX70JJdqfGhiQVPZNVIyPQ>?MXSyOVI{QTl|NR?=
SUDHL14NGfTe2JCeG:ydH;zbZMhSXO|c3H5NIDI[nIzNjYkgKOzMlUhdk1?MUW0PEBpMX\lcohidmOnczD0bIUh[2WubDDk[YF1cCClbz30doVifG2nboSge4l1cCCDQ2mxNlE2M2rvUVI2OjN7OUO1
U2932NEm5O2JCeG:ydH;zbZMhSXO|c3H5MoHQNk426oDVMz61JI5ONVz6NYJkPDhiaB?=M4HvcYVvcGGwY3XzJJRp\SClZXzsJIRm[XSqIHPvMZRz\WG2bXXueEB4cXSqIFHDXVEzOTV?MX[yOVI{QTl|NR?=
P-UMSCC-1NH24bGxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NVLGTYV1UUN3ME2xNU4zKG6PMXeyOFkyPTB|OR?=
R-UMSCC-1MkDVS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MVLJR|UxRTJ{OUSgcm0>MlXFNlQ6OTVyM{m=
P-Cal33MXrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MVvJR|UxRTF5LkOgcm0>NFK5XJozPDlzNUCzPS=>
R-Cal33M33aVmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7NV;LWZQzUUN3ME2xNVEzKG6PM4HkW|I1QTF3MEO5
JurkatNFzOeI9Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?=M4ezOVEuOTGwTR?=NH\FfY01QCCqMnm2bY5pcWKrdIOgeIhmKGOnbHygdJJwdGmoZYLheIlwdiClbz30doVifG2nboSge4l1cCC4b4Lpco9{fGG2M13zflI1QDBzMUK4
JurkatM4LBdGFxd3C2b4Ppd{BCe3O|YYm=NFL5TZM5KG6PNUfsfYFYOjRxNEigbC=>NEO1ZlRqdmS3Y3XzJIFxd3C2b4Ppd{wh[2G|cHHz[UBi[3SrdnH0bY9vNCCjbnSgVGFTWCClbHXheoFo\SClbz30doVifG2nboSge4l1cCC4b4Lpco9{fGG2NXWxWY9wOjR6MEGxNlg>
UMSCC-22ANV;YfHpbSXCxcITvd4l{KEG|c4PhfS=>NXHOV29OOjByIH7NMljaNlQhcA>?MmO5bY5lfWOnIITo[UBk\WyuIHHwc5B1d3OrczDjc{11emWjdH3lcpQhf2m2aDDPUnghODlzMh?=MkS2NlI6Ojl6MEO=
UMSCC-22BM2DWdmFxd3C2b4Ppd{BCe3O|YYm=MV2yNFAhdk1?M3z2d|I1KGh?MkO5bY5lfWOnIITo[UBk\WyuIHHwc5B1d3OrczDjc{11emWjdH3lcpQhf2m2aDDPUnghODlzMh?=M{TzelIzQTJ7OECz
1483NWTZTYt[SXCxcITvd4l{KEG|c4PhfS=>M3zoNFIxOCCwTR?=NF;nSpgzPCCqMlTObY5lfWOnIITo[UBk\WyuIHHwc5B1d3OrczDjc{11emWjdH3lcpQhf2m2aDDPUnghODlzMh?=MWCyNlkzQThyMx?=
UMSCC-1NIfxPINCeG:ydH;zbZMhSXO|c3H5NF3RboYzODBibl2=MV[yOEBpNE\lZmNqdmS3Y3WgeIhmKGOnbHygZZBweHSxc3nzJINwNXS{ZXH0cYVvfCC5aYToJG9PYCByOUGyMoCxNlI6Ojl6MEO=
UMSCC-22ANX33PXRFT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=MXvJR|UxRTN6LkegxtEhOS5yIH7NNF7xRZUzOjl{OUiwNy=>
UMSCC-22BNXzBZWFXT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NXS0U|V2UUN3ME2zNE44KMLzIEmuN{BvVQ>?NEDnT2IzOjl{OUiwNy=>
1483NULZeZg6T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NHzsPHFKSzVyPUWwMlUhyrFiMUGuPUBvVQ>?M{fLU|IzQTJ7OECz
UMSCC-1NE\pR2ZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NWrmVo9RUUN3ME2zOE43KMLzIEKuOkBvVQ>?NFS1ZlIzOjl{OUiwNy=>
Cal33MkHZS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?M{i3fGlEPTB;NEmuN{DDuSB6Lkmgcm0>M4r3fFIzQTJ7OECz
PCI-15ANVPBWZUxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NU\LTWpUUUN3ME23NE41KMLzIEKyMlYhdk1?NG\HOoMzOjl{OUiwNy=>
PCI-15BNXXjOmJUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=MlvlTWM2OD1|OT61JOKyKDFzLkCgcm0>NIXQSGMzOjl{OUiwNy=>
OSC-19NX3ZNlY5T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M1;ubmlEPTB;MUiuN{DDuSB2LkKgcm0>MXKyNlkzQThyMx?=
SUDHL16M2rONGFxd3C2b4Ppd{BCe3O|YYm=NYXkcW5kOi5yLUSuNEBvVQ>?M{DRZ|Q5KGh?NGj2PWtqdmS3Y3XzJINmdGxiZHXheIgh[29vdILlZZRu\W62IIfpeIghd2KjdH;jcIF5MnrnNlI1OTF6OUm=
SUDHL16MlLxSpVv[3Srb36gRZN{[Xl?NFOwN5MzNjVibl2=MkTINlQhcA>?M3zhOIFkfGm4YYTld{BLVktuIHnuZYN1cX[jdHXzJGFMXCxidYCtdoVofWyjdHXzJG5wgGFuIHHu[EBqdmS3Y3XzJO6{UDKDLmigZ48ufHKnYYTt[Y51KHerdHigc4JifG:lbHH4NGTMUpUzOjRzMUi5PS=>
GrantaMoXNS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?M3;xc|AuPCCwTR?=M{Wyc|Q5KGh?NYHCfpBIcW6mdXPlJINmdGxiZHXheIgh[29vdILlZZRu\W62IIfpeIghUEGGQ1nzNYHLWZg3OjF5NUCyNlQ>
SUDHL16NH\oXWhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NVnVdYV2OS12IH7NM{LsclM3KGh?MkT1bY5lfWOnIHPlcIwh\GWjdHigZ48ufHKnYYTt[Y51KHerdHigTGFFS0m|M{PSVlIxOjN|OUez

... Click to View More Cell Line Experimental Data

In vivo 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]
Features

Protocol(Only for Reference)

Kinase Assay: [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.

Cell Assay: [1]

Cell lines WST-1, ANBL-6 cells
Concentrations 100 nM
Incubation Time 1 hour
Method 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.

Animal Study: [4]

Animal Models Beige-nude-XID mice
Formulation 10% sulfobutylether β-cyclodextrin in 10 mmol/L citrate buffer pH 3.5,
Dosages 2.0 mg/kg
Administration i.v.

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

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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

References

[1] Kuhn DJ, et al. Blood. 2007, 110(9), 3281-3290.

[2] Kuhn DJ, et al. Curr Cancer Drug Targets. 2011, 11(3), 285-295.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02802163 Not yet recruiting Multiple Myeloma H. Lee Moffitt Cancer Center and Research Institute|Novar  ...more H. Lee Moffitt Cancer Center and Research Institute|Novartis|Amgen September 2016 Phase 1|Phase 2
NCT02756663 Not yet recruiting Multiple Myeloma Novartis Pharmaceuticals|Novartis June 2016 Phase 2
NCT02659293 Recruiting Multiple Myeloma University of Chicago April 2016 Phase 3
NCT02293109 Recruiting Contiguous Stage II Adult Lymphoblastic Lymphoma|Noncontiguous Stage II Adult Lymphoblastic Lymphoma|Stage I Adult Lymphoblastic Lymphoma|Stage III  ...more Contiguous Stage II Adult Lymphoblastic Lymphoma|Noncontiguous Stage II Adult Lymphoblastic Lymphoma|Stage I Adult Lymphoblastic Lymphoma|Stage III Adult Lymphoblastic Lymphoma|Stage IV Adult Lymphoblastic Lymphoma|Untreated Adult Acute Lymphoblastic Leukemia University of California, Davis|Onyx Pharmaceuticals December 2015 Phase 1
NCT02628704 Not yet recruiting Multiple Myeloma Karyopharm Therapeutics, Inc December 2015 Phase 2

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Chemical Information

Download Carfilzomib (PR-171) SDF
Molecular Weight (MW) 719.91
Formula

C40H57N5O7

CAS No. 868540-17-4
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 50 mg/mL (69.45 mM)
Water <1 mg/mL (<1 mM)
Ethanol <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.
Chemical Name L-Phenylalaninamide, (αS)-α-[[2-(4-morpholinyl)acetyl]amino]benzenebutanoyl-L-leucyl-N-[(1S)-3-methyl-1-[[(2R)-2-methyl-2-oxiranyl]carbonyl]butyl]-

Frequently Asked Questions

  • Question 1
    How should I prepare solution of Carfilzomib for ongoing in vivo study?

    Answer: 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.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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