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| Targets |
Immunoproteasome subunit LMP-7 (low molecular mass protein-7, also known as beta5i or PSMB8), a catalytic subunit of the immunoproteasome. The immunoproteasome is a specialized form of the proteasome expressed primarily in hematopoietic cells and is induced by interferon-gamma. LMP-7 is the chymotrypsin-like catalytic site of the immunoproteasome. PR-924 is a selective tripeptide epoxyketone inhibitor that covalently binds to the N-terminal threonine active site of LMP-7, blocking its proteolytic activity.
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| ln Vitro |
In vitro, PR-924 selectively inhibits the immunoproteasome subunit LMP-7 with an IC50 of 22 nM. It shows selectivity for the immunoproteasome over the constitutive proteasome, which is important for reducing off-target effects in non-immune cells. PR-924 inhibits the growth of multiple myeloma (MM) cells and triggers apoptosis in a dose-dependent manner. The (R)-isomer serves as a reference control to confirm the specificity of the active compound.
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| ln Vivo |
In vivo, PR-924 blocks multiple myeloma cell growth in both in vitro and in vivo models. In multiple myeloma xenograft mouse models, PR-924 treatment results in significant tumor growth inhibition and apoptosis induction in tumor tissues. The compound also shows activity in other hematologic malignancies that are dependent on immunoproteasome function. The (R)-isomer is used as a control to validate that these effects are mediated by specific LMP-7 inhibition.
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| Enzyme Assay |
For immunoproteasome activity assays, purified 20S immunoproteasome or cell lysates are incubated with a fluorogenic substrate specific for the chymotrypsin-like activity (e.g., Suc-LLVY-AMC, 40 uM) in assay buffer (20 mM HEPES, pH 7.5, 0.5 mM EDTA, 0.035% SDS) at 37degC for 60 minutes. Varying concentrations of test compound are pre-incubated with the enzyme for 15 minutes. Fluorescence (λ_ex 380 nm, λ_em 460 nm) is measured, and IC50 values are calculated. PR-924 shows IC50 of 22 nM for LMP-7.
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| Cell Assay |
Cell viability assays are performed in multiple myeloma cell lines (e.g., MM.1S, RPMI-8226, U266, KMS-11). Cells are seeded in 96-well plates and treated with serial dilutions of active PR-924 or the (R)-isomer as control for 48-72 hours. Cell viability is measured using MTT, CCK-8, or CellTiter-Glo assays. Apoptosis is assessed by flow cytometry using Annexin V/PI staining and by measuring caspase-3/7 activity. Proteasome activity in cell lysates is also measured using fluorogenic substrates to confirm target engagement.
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| Animal Protocol |
In vivo efficacy studies are performed in subcutaneous multiple myeloma xenograft models. Female SCID or NOD/SCID mice are implanted with MM.1S or RPMI-8226 cells. When tumors reach approximately 150-200 mm3, mice are randomized and treated with PR-924 (doses 5-20 mg/kg) or the (R)-isomer as control, typically administered intravenously or intraperitoneally on a schedule of QD x 14 days or QOD. Tumor volumes are measured by calipers twice weekly. Body weight is monitored as a toxicity indicator. At endpoint, tumors are collected for Western blot analysis of PARP cleavage and proteasome activity assays.
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| ADME/Pharmacokinetics |
As a research control isomer, PK data for (R)-PR-924 is not publicly available. The active parent compound PR-924 is a tripeptide epoxyketone that is structurally related to carfilzomib (Kyprolis®), an FDA-approved proteasome inhibitor for multiple myeloma. Carfilzomib has an intravenous half-life of approximately 30-60 minutes in humans, moderate volume of distribution, and is primarily metabolized by peptidase cleavage and epoxide hydrolysis. PR-924 is expected to have similar properties as a research tool compound.
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| Toxicity/Toxicokinetics |
The (R)-isomer is non-toxic at control concentrations. For the active PR-924, in preclinical toxicology studies, the most common adverse effects are related to proteasome inhibition, including gastrointestinal disturbances, fatigue, and hematologic effects. Unlike carfilzomib which inhibits both the constitutive proteasome and immunoproteasome, PR-924's selectivity for LMP-7 may reduce certain toxicities. However, as a research compound, comprehensive toxicology data for PR-924 is limited. No information on chronic toxicity or genotoxicity is publicly available.
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| References |
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| Additional Infomation |
PR-924 and the control isomer (R)-PR-924 are research-grade chemicals used for immunoproteasome biology studies. The immunoproteasome has emerged as an attractive drug target for hematologic malignancies and autoimmune diseases. Carfilzomib (Kyprolis®) and ixazomib (Ninlaro®) are FDA-approved proteasome inhibitors for multiple myeloma, but they target multiple proteasome subunits. Selective immunoproteasome inhibitors like PR-924 may offer improved therapeutic windows. These products are for research use only and have not been approved for human therapy.
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| Molecular Formula |
C37H38N4O5
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| Molecular Weight |
618.72
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| Related CAS # |
PR-924;1416709-79-9
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| Appearance |
White to off-white solid powder
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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 |
| 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) |
DMSO :~125 mg/mL (~202.03 mM)
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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 | 1.6162 mL | 8.0812 mL | 16.1624 mL | |
| 5 mM | 0.3232 mL | 1.6162 mL | 3.2325 mL | |
| 10 mM | 0.1616 mL | 0.8081 mL | 1.6162 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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