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| Targets |
Carfilzomib-d8 targets the proteasome, specifically the chymotrypsin-like activity of the 20S proteasome. Carfilzomib is an irreversible proteasome inhibitor that binds covalently to the catalytic threonine residue in the proteasome active site via its epoxyketone pharmacophore. This mechanism places the compound within the proteasome pathway and the apoptosis pathway. By inhibiting proteasome function, Carfilzomib prevents the degradation of pro-apoptotic factors and promotes the accumulation of misfolded proteins, leading to endoplasmic reticulum stress and apoptosis in cancer cells, particularly multiple myeloma cells.
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| ln Vitro |
Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1].
In vitro, Carfilzomib demonstrates potent proteasome inhibition with an IC₅₀ of 5 nM in ANBL-6 and RPMI 8226 multiple myeloma cell lines. The compound irreversibly inhibits the chymotrypsin-like activity of the proteasome, leading to the accumulation of ubiquitinated proteins and induction of apoptosis. Carfilzomib-d8, as the deuterated analog, is used as an internal standard in cell-based studies to quantify Carfilzomib concentrations in cell lysates and culture media. The deuterated form enables accurate measurement of drug uptake and intracellular accumulation in various cancer cell lines. |
| ln Vivo |
Carfilzomib-d8 is used in vivo as a deuterated internal standard for pharmacokinetic studies of Carfilzomib. Carfilzomib itself has demonstrated antitumor activity in multiple myeloma xenograft models and is clinically approved for the treatment of relapsed or refractory multiple myeloma. In vivo, Carfilzomib induces tumor regression through proteasome inhibition, resulting in the accumulation of pro-apoptotic proteins and suppression of NF-κB signaling. The deuterated form is employed in LC-MS/MS methods to accurately quantify parent drug concentrations in plasma and tissues during preclinical and clinical pharmacokinetic studies.
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| Enzyme Assay |
In vitro enzyme assays for Carfilzomib involve measuring proteasome activity using fluorogenic substrates. The standard protocol includes incubating purified 20S proteasome or cell lysates with varying concentrations of Carfilzomib (0-100 nM) and a fluorogenic substrate such as Suc-LLVY-AMC (for chymotrypsin-like activity). Fluorescence is measured over time to determine the rate of substrate cleavage, and IC₅₀ values are calculated from dose-response curves. For the deuterated form, it is used as an internal standard in LC-MS-based binding or activity assays to quantify Carfilzomib concentrations.
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| Cell Assay |
Cell-based assays for Carfilzomib are conducted in multiple myeloma cell lines such as ANBL-6 and RPMI 8226. Cells are treated with Carfilzomib at concentrations ranging from 0.1-100 nM for 24-72 hours. Cell viability is assessed using MTT or CellTiter-Glo assays. Apoptosis is evaluated by Annexin V staining, caspase activation, and PARP cleavage. Proteasome activity in cell lysates is measured using fluorogenic substrates. The deuterated analog is used as an internal standard for LC-MS/MS quantification of Carfilzomib in cell lysates to correlate intracellular drug concentrations with biological effects.
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| Animal Protocol |
In vivo animal experiments for Carfilzomib typically use mouse xenograft models of multiple myeloma. Animals are administered Carfilzomib via intravenous injection at doses of 1-5 mg/kg on schedules such as days 1-2 of each week. Tumor volume is measured periodically, and body weight is monitored. At study termination, plasma and tumor tissues are collected for pharmacokinetic and pharmacodynamic analysis. The deuterated analog, Carfilzomib-d8, is used as an internal standard in LC-MS/MS methods for the quantification of Carfilzomib in these biological samples.
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| ADME/Pharmacokinetics |
Carfilzomib-d8 is used as an internal standard for pharmacokinetic studies of Carfilzomib. Carfilzomib has a short half-life due to rapid proteasome binding and metabolism, with typical PK parameters including a volume of distribution of approximately 28 L, clearance of 150-200 L/h, and a terminal half-life of less than 1 hour. The deuterated form provides a mass shift of +8 Da relative to the non-deuterated compound, allowing simultaneous detection by mass spectrometry. Storage: powder at -20°C for 3 years; in solvent at -80°C for 6 months. Solubility: DMF 15 mg/mL, DMSO 15 mg/mL, Ethanol 1 mg/mL.
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| Toxicity/Toxicokinetics |
Carfilzomib-d8 is supplied for research use only and is not intended for human administration. The non-deuterated parent compound, Carfilzomib, is a clinically approved drug (Kyprolis®) for the treatment of multiple myeloma. Common adverse effects include fatigue, nausea, anemia, thrombocytopenia, and cardiotoxicity. The deuterated form is used in trace quantities as an analytical standard. Standard laboratory safety precautions should be followed. Storage requires protection from light and moisture.
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| References |
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| Additional Infomation |
Carfilzomib-d8 (CAS 1537187-53-3) is a stable isotope-labeled compound used as an internal standard for the quantification of Carfilzomib. It is not intended for therapeutic use. Carfilzomib is a clinically approved proteasome inhibitor (Kyprolis®) for the treatment of relapsed or refractory multiple myeloma. The deuterium labeling is at the morpholine ring positions. Purity is typically >98%. The compound is for research and analytical applications only.
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| Molecular Formula |
C40H57N5O7
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|---|---|
| Molecular Weight |
727.959184408188
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| Exact Mass |
727.476
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| CAS # |
1537187-53-3
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| Related CAS # |
Carfilzomib;868540-17-4
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| PubChem CID |
72944553
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
975.6±65.0 °C at 760 mmHg
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| Flash Point |
543.8±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.551
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| LogP |
6.71
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
20
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| Heavy Atom Count |
52
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| Complexity |
1180
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| Defined Atom Stereocenter Count |
5
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| SMILES |
[2H]C1(C(OC(C(N1CC(=O)N[C@@H](CCC2=CC=CC=C2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC3=CC=CC=C3)C(=O)N[C@@H](CC(C)C)C(=O)[C@]4(CO4)C)([2H])[2H])([2H])[2H])([2H])[2H])[2H]
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| InChi Key |
BLMPQMFVWMYDKT-HEMZLDBQSA-N
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| InChi Code |
InChI=1S/C40H57N5O7/c1-27(2)22-32(36(47)40(5)26-52-40)42-39(50)34(24-30-14-10-7-11-15-30)44-38(49)33(23-28(3)4)43-37(48)31(17-16-29-12-8-6-9-13-29)41-35(46)25-45-18-20-51-21-19-45/h6-15,27-28,31-34H,16-26H2,1-5H3,(H,41,46)(H,42,50)(H,43,48)(H,44,49)/t31-,32-,33-,34-,40+/m0/s1/i18D2,19D2,20D2,21D2
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| Chemical Name |
(2S)-4-methyl-N-[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]-2-[[(2S)-2-[[2-(2,2,3,3,5,5,6,6-octadeuteriomorpholin-4-yl)acetyl]amino]-4-phenylbutanoyl]amino]pentanamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3737 mL | 6.8685 mL | 13.7370 mL | |
| 5 mM | 0.2747 mL | 1.3737 mL | 2.7474 mL | |
| 10 mM | 0.1374 mL | 0.6869 mL | 1.3737 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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