Bortezomib (PS-341)

Catalog No.S1013

Bortezomib (PS-341) is a potent 20S proteasome inhibitor with Ki of 0.6 nM in a cell-free assay.

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Bortezomib (PS-341) Chemical Structure

Bortezomib (PS-341) Chemical Structure
Molecular Weight: 384.24

Validation & Quality Control

Cited by 142 publications:

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Quality Control & MSDS

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Product Information

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  • Research Area
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description Bortezomib (PS-341) is a potent 20S proteasome inhibitor with Ki of 0.6 nM in a cell-free assay.
Targets 20S proteasome [1]
(Cell-free assay)
IC50 0.6 nM(Ki)
In vitro Bortezomib, a boronic acid dipeptide, is a highly selective, reversible inhibitor of the 26S proteasome which primarily functions in the degradation of mis-folded proteins and is essential for the regulation of the cell cycle. Exposure to Bortezomib has been shown to stabilize p21, p27, and p53, as well as the proapoptotic Bid and Bax proteins, caveolin-1, and inhibitor κB-α, which prevents activation of nuclear factor κB-induced cell survival pathways. Bortezomib also promotes the activation of the proapoptotic c-Jun-NH2 terminal kinase, as well as the endoplasmic reticulum stress response. Alteration of the levels of these cellular proteins leads to inhibition of proliferation, migration, and promotion of apoptosis of cancer cells. [2] Bortezomib is shown to penetrate into cells and inhibit proteasome-mediated intracellular proteolysis of long-lived proteins with a concentration that inhibits 50% of the proteolysis of ∼0.1 μM. The average growth inhibition of 50% value for Bortezomib across the entire panel of 60 cancer cell lines derived from multiple human tumors from the US National Cancer Institute (NCI) is 7 nM. Treatment of PC-3 cells with Bortezomib (100 nM) for 8 h results in the accumulation of cells in G2-M, with a corresponding decrease in the number of cells in G1. Bortezomib kills PC-3 cells at 24 and 48 hr with IC50 of 100 and 20 nM, respectively. Bortezomib induces nuclear condensation at 16–24 hr after treatment. Bortezomib treatment leads to PARP cleavage in a time-dependent manner with concentrations as low as 100 nM being effective at 24 hr. [1]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
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... Click to View More Cell Line Experimental Data

In vivo The anticancer effects of bortezomib as a single agent have been demonstrated in xenograft models of multiple myeloma, adult T-cell leukemia, lung, breast, prostate, pancreatic, head and neck, and colon cancer, and in melanoma. [2] Oral bortezomib 1.0 mg/ kg daily for 18 days causes tumor growth delays, as well as a decrease in the number of metastases in the Lewis lung cancer model. Bortezomib at a single dose of up to 5 mg/kg significantly decreased the surviving fraction of breast tumor cells. Bortezomib 1.0 mg/kg administrated weekly for 4 weeks reduces tumor growth by 60% in murine xenograft models of prostate cancer. 1.0 mg/kg Bortezomib administration for 4 weeks results in a 72% or 84% reduction in pancreatic cancer murine xenografts growth, as well as an increase in tumor cell apoptosis. 1.0 mg/kg Bortezomib treatment results in significant inhibition of human plasmacytoma xenograft growth, increase in tumor cells apoptosis and overall survival, and a decrease in tumor angiogenesis. [3]
Features

Protocol(Only for Reference)

Kinase Assay:

[4]

Kinetic Methods In a typical kinetic run, 2.00 mL of assay buffer (20 mM HEPES, 0.5 mM EDTA, 0.035% SDS, pH 7.8) and Suc-Leu-Leu-Val-Tyr-AMC in DMSO are added to a 3 mL fluorescence cuvette, and the cuvette is placed in the jacketed cell holder of a fluorescence spectrophotometer. Reaction temperature is maintained at 37℃ by a circulating water bath. After the reaction solution has reached thermal equilibrium (5 minutes), 1 μL−10 μL of the stock enzyme solution is added to the cuvette. Reaction progress is monitored by the increase in fluorescence emission at 440 nm (λex= 380 nm) that accompanies cleavage of AMC from peptide-AMC substrates.

Cell Assay:

[5]

Cell lines Human multiple myeloma cells line U266
Concentrations ~10 μM
Incubation Time 2 days
Method

The inhibitory effect of Bortezomib on cell growth is assessed by measuring MTT dye absorbance of the cells. Cells from 48-hour cultures are pulsed with 10 μL of 5 mg/mL MTT to each well for the last 4 hour of 48-hour cultures, followed by 100 μL of isopropanol containing 0.04 N HCl. Absorbance is measured at 570 nm using a spectrophotometer.

Animal Study:

[3]

Animal Models Human plasmacytoma xenografts RPMI 8226
Formulation Saline
Dosages 1 mg/kg
Administration i.v. twice weekly for 4 weeks, then once weekly

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] Adams J, et al. Cancer Res, 1999, 59(11), 2615-2622.

[2] Boccadoro M, et al. Cancer Cell Int, 2005, 5(1):18.

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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
NCT02658396 Not yet recruiting Multiple Myeloma|Multiple Myeloma in Relapse|Refractory Multiple Myeloma Dana-Farber Cancer Institute|Genus Oncology, LLC|National  ...more Dana-Farber Cancer Institute|Genus Oncology, LLC|National Institutes of Health (NIH) December 2016 Phase 1
NCT02811978 Not yet recruiting Multiple Myeloma Janssen Research & Development, LLC September 2016 Phase 3
NCT02840539 Not yet recruiting Mantle Cell Lymphoma Seoul National University Hospital|Consortium for Improvi  ...more Seoul National University Hospital|Consortium for Improving Survival of Lymphoma August 2016 Phase 2
NCT02719613 Recruiting Multiple Myeloma Bristol-Myers Squibb|AbbVie July 2016 Phase 2
NCT02755597 Recruiting Relapsed/Refractory Multiple Myeloma AbbVie|Genentech, Inc. July 2016 Phase 3

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Chemical Information

Download Bortezomib (PS-341) SDF
Molecular Weight (MW) 384.24
Formula

C19H25BN4O4

CAS No. 179324-69-7
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms LDP-341, MLM341
Solubility (25°C) * In vitro DMSO 76 mg/mL (197.79 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 2% DMSO+30% PEG 300+ddH2O 5mg/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 B-​[(1R)​-​3-​methyl-​1-​[[(2S)​-​1-​oxo-​3-​phenyl-​2-​[(2-​pyrazinylcarbonyl)​amino]​propyl]​amino]​butyl]​-boronic acid

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