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Carfilzomib (PR-171)

Proteasome inhibitor,epoxomicin analog CAS# 868540-17-4

Carfilzomib (PR-171)

Catalog No. BCC1145----Order now to get a substantial discount!

Product Name & Size Price Stock
Carfilzomib (PR-171):10mg $144.00 In stock
Carfilzomib (PR-171):20mg $245.00 In stock
Carfilzomib (PR-171):50mg $576.00 In stock
Carfilzomib (PR-171):100mg $1008.00 In stock
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Chemical structure

Carfilzomib (PR-171)

3D structure

Chemical Properties of Carfilzomib (PR-171)

Cas No. 868540-17-4 SDF Download SDF
PubChem ID 11556711 Appearance Powder
Formula C40H57N5O7 M.Wt 719.91
Type of Compound N/A Storage Desiccate at -20°C
Synonyms PR-171
Solubility DMF : ≥ 100 mg/mL (138.91 mM)
DMSO : 50 mg/mL (69.45 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
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-morpholin-4-ylacetyl)amino]-4-phenylbutanoyl]amino]pentanamide
SMILES CC(C)CC(C(=O)C1(CO1)C)NC(=O)C(CC2=CC=CC=C2)NC(=O)C(CC(C)C)NC(=O)C(CCC3=CC=CC=C3)NC(=O)CN4CCOCC4
Standard InChIKey BLMPQMFVWMYDKT-NZTKNTHTSA-N
Standard InChI 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
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Carfilzomib (PR-171)

DescriptionCarfilzomib (PR-171) is an irreversible inhibitor of proteasome with IC50 of <5 nM.
TargetsProteasome    
IC505 nM     

Protocol

Cell experiment [1]:

Cell lines

HT-29 colorectal adenocarcinoma cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

1 h; IC50=9 nM

Applications

Incubation of HT-29 colorectal adenocarcinoma cells with PR-171 for 1 h resulted in a dose-dependent inhibition of all three proteasome catalytic activities with the chymotrypsin-like activity exhibiting the greatest sensitivity (IC50=9 nM). The caspase-like and trypsin-like activities were inhibited to a greater extent in the cellular assay (IC50=150–200 nM) than in the isolated enzyme assay (IC50>1 μM).

Animal experiment [1]:

Animal models

BNX mice

Dosage form

5 mg/kg delivered weekly; QDx2; intravenous injection

Application

The antitumor activity of PR-171 was evaluated in BNX mice bearing established human tumor xenografts derived from three tumor cell lines: HT-29 (colorectal adenocarcinoma), RL (B cell lymphoma ), and HS-Sultan (Burkitt’s lymphoma). All PR-171 dosing schedules (up to 5 mg/kg delivered weekly QDx2) were tolerated in the tumor-bearing animals, resulting in weight loss of <10%. The results show that the activity of PR-171 is dose and schedule dependen. And PR-171 also suppressed proteasome activity in blood and adrenals.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Demo S D, Kirk C J, Aujay M A, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome[J]. Cancer research, 2007, 67(13): 6383-6391.

Carfilzomib (PR-171) Dilution Calculator

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Preparing Stock Solutions of Carfilzomib (PR-171)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.3891 mL 6.9453 mL 13.8906 mL 27.7813 mL 34.7266 mL
5 mM 0.2778 mL 1.3891 mL 2.7781 mL 5.5563 mL 6.9453 mL
10 mM 0.1389 mL 0.6945 mL 1.3891 mL 2.7781 mL 3.4727 mL
50 mM 0.0278 mL 0.1389 mL 0.2778 mL 0.5556 mL 0.6945 mL
100 mM 0.0139 mL 0.0695 mL 0.1389 mL 0.2778 mL 0.3473 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of Carfilzomib (PR-171)

1. Carfilzomib: a novel agent for multiple myeloma. J Pharm Pharmacol. 2013 Aug;65(8):1095-106. doi: 10.1111/jphp.12072. Epub 2013 Apr 24.
Abstract
Carfilzomib has been review as a new agent to treat relapsed and refractory MM.
2. A novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant anti-myeloma activity. Leukemia. 2014 Feb 12. doi: 10.1038/leu.2014.69. [Epub ahead of print]
Abstract
Instead of inhibiting the formation of OC sealing zone alone, the combination of cartfilzomib and CC-292 exhibited synergistic anti-MM activities, including inhibition of both sealing zone formation and differentiation of OC, suppression of tumor burden in a mouse model and increasing bone volume.
3. In vitro and in vivo therapeutic efficacy of carfilzomib in mantle cell lymphoma: targeting the immunoproteasome. Mol Cancer Ther. 2013 Nov;12(11):2494-504. doi: 10.1158/1535-7163.MCT-13-0156. Epub 2013 Aug 29.
Abstract
Carfilzomib, a proteasome inhibitor, is an anti-MCL agent that concentration-dependently inhibited cell growth, induced apoptosis and suppressed survival signaling pathways NF-KB and STAT3 without causing toxicity to normal peripheral blood mononuclear cells. Immunoproteasome, particularly LMP2, plays an indispensible role in anti-MCL activity of carfilzomib.
4. Carfilzomib-Associated Tumor Lysis Syndrome. Pharmacotherapy. 2014 Jan 4. doi: 10.1002/phar.1397. [Epub ahead of print]
Abstract
Even though it is an FDA-approved anti-MM drug with less than 1% TLS frequency, carfilzomib has been associated with TLS development in a 55-year-old male patient with relapsed MM.
5. Carfilzomib: a second-generation proteasome inhibitor for the treatment of relapsed and refractory multiple myeloma. Ann Pharmacother. 2013 Jan;47(1):56-62. doi: 10.1345/aph.1R561. Epub 2013 Jan 8.
Abstract
Carfilzomib, an FDA-approved anti-MM drug, has been evaluated in the treatment of patients who have relapsed and refractory MM and received prior bortezomib and thalidomide or lenalidomide.

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Background on Carfilzomib (PR-171)

An epoxomicin derivate with potential antineoplastic activity. It irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome, an enzyme responsible for degrading a large variety of cellular proteins. Inhibition of proteasome-mediated proteolysis results in an accumulation of polyubiquinated proteins, which may lead to cell cycle arrest, induction of apoptosis, and inhibition of tumor growth.

References:
1. Guido Cavaletti, et al., Leukemia & Lymphoma (2010), 51(7), 1178-1187.
2. Girija Dasmahapatra, et al., Blood (2010), 115(22), 4478-4487.

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References on Carfilzomib (PR-171)

A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies.[Pubmed:19903785]

Clin Cancer Res. 2009 Nov 15;15(22):7085-91.

PURPOSE: Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib. EXPERIMENTAL DESIGN: In a phase 1 trial evaluating the safety and efficacy of carfilzomib in relapsed or refractory hematologic malignancies, eight dose groups of three to six patients received 5 consecutive days of carfilzomib i.v. push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, and 20 mg/m2 within 14-day cycles. RESULTS: Twenty-nine patients enrolled that were relapsed or refractory after at least two prior therapies. Nonhematologic toxicities included fatigue, nausea, and diarrhea in more than one third of patients-mostly grade 1 or 2 in severity. At 20 mg/m2, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses > or =11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenstrom's macroglobulinemia). CONCLUSION: This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologic malignancies using consecutive-day dosing.

Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas.[Pubmed:26284612]

Leuk Lymphoma. 2016;57(3):635-43.

A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30-min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3 + 3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m2 carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and two patients had stable disease. Correlative studies showed a decrease in NF-kappaB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response.

Description

Carfilzomib is an irreversible proteasome inhibitor with an IC50 of 5 nM in ANBL-6 and RPMI 8226 cells.

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