WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 200630
CAS#: 868540-17-4
Description: Carfilzomib, also known as PR-171, is a tetrapeptide epoxyketone and an epoxomicin derivate with potential antineoplastic activity. Carfilzomib 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. Carfilzomib was approved by the FDA for use in patients with relapsed and refractory multiple myeloma on 20 July 2012.
MedKoo Cat#: 200630
Name: Carfilzomib
CAS#: 868540-17-4
Chemical Formula: C40H57N5O7
Exact Mass: 719.4258
Molecular Weight: 719.91
Elemental Analysis: C, 66.73; H, 7.98; N, 9.73; O, 15.56
Synonym: PR171; PR-171; PR 171; Carflizomib. brand name: Kyprolis
IUPAC/Chemical Name: (S)-4-methyl-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylamino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide
InChi Key: BLMPQMFVWMYDKT-NZTKNTHTSA-N
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
SMILES Code: CC(C)C[C@H](NC([C@@H](NC(CN1CCOCC1)=O)CCC2=CC=CC=C2)=O)C(N[C@@H](CC3=CC=CC=C3)C(N[C@@H](CC(C)C)C([C@]4(C)OC4)=O)=O)=O.
Appearance: white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | Carfilzomib (PR-171) is a proteasome inhibitor with an IC50 of 5 nM in ANBL-6 and RPMI 8226 cells. |
| In vitro activity: | Carfilzomib induced growth inhibition and apoptosis in both established mantle cell lymphoma (MCL) cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells was mediated by the activation of JNK, Bcl-2, and mitochondria-related pathways. In addition, carfilzomib inhibited the growth and survival signaling pathways NF-κB and STAT3. Interestingly, it was discovered that expression of immunoproteasome (i-proteasome) subunits is required for the anti-MCL activity of carfilzomib in MCL cells. Reference: Mol Cancer Ther. 2013 Nov;12(11):2494-504. https://mct.aacrjournals.org/content/12/11/2494.long |
| In vivo activity: | To examine the anti-MCL effects of carfilzomib in vivo, an MCL-bearing SCID mouse model was used first. Mino cells (5 ×106 cells per mouse) were subcutaneously inoculated into the right flank of SCID mice. When palpable tumors developed (≥3 mm in diameter), mice (6 per group) received either an intravenous injection of carfilzomib (5 mg/kg) or vehicle control twice a week for 5 weeks. Tumor growth was measured weekly until the tumor diameter reached 15 mm. Carfilzomib almost abrogated tumor growth (Fig. 6A, P < 0.01). Furthermore, carfilzomib significantly prolonged the survival time of the tumor-bearing mice (P < 0.01, Fig. 6B). In the primary MCL-bearing SCID-hu mouse model, one injection of 5 × 106 freshly isolated primary MCL cells was injected directly into human fetal bone implanted within the SCID-hu hosts. The level of circulating human β2M in mouse serum was used to monitor tumor burden in the SCID-hu mice. The intravenous administration of 5 mg/kg carfilzomib on days 1 and 2 per week, for 5 weeks inhibited tumor growth and prolonged survival in the primary MCL-bearing SCID-hu mice (P < 0.01, Fig. 6C and D). Reference: Mol Cancer Ther. 2013 Nov;12(11):2494-504. https://mct.aacrjournals.org/content/12/11/2494.long |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 59.25 | 82.3 | |
| DMF | 57.5 | 79.87 | |
| Ethanol | 7.7 | 10.7 |
The following data is based on the product molecular weight 719.91 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Zhang L, Pham LV, Newberry KJ, Ou Z, Liang R, Qian J, Sun L, Blonska M, You Y, Yang J, Lin X, Rollo A, Tamayo AT, Lee J, Ford RJ, Zhao X, Kwak LW, Yi Q, Wang M. 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. PMID: 23990113. |
| In vitro protocol: | 1. Zhang L, Pham LV, Newberry KJ, Ou Z, Liang R, Qian J, Sun L, Blonska M, You Y, Yang J, Lin X, Rollo A, Tamayo AT, Lee J, Ford RJ, Zhao X, Kwak LW, Yi Q, Wang M. 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. PMID: 23990113. |
| In vivo protocol: | 1. Zhang L, Pham LV, Newberry KJ, Ou Z, Liang R, Qian J, Sun L, Blonska M, You Y, Yang J, Lin X, Rollo A, Tamayo AT, Lee J, Ford RJ, Zhao X, Kwak LW, Yi Q, Wang M. 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. PMID: 23990113. |
1: Kim KB, Crews CM. From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes. Nat Prod Rep. 2013 May;30(5):600-4. doi: 10.1039/c3np20126k. Review. PubMed PMID: 23575525; PubMed Central PMCID: PMC3815659.
2: Kortuem KM, Stewart AK. Carfilzomib. Blood. 2013 Feb 7;121(6):893-7. doi: 10.1182/blood-2012-10-459883. Review. PubMed PMID: 23393020.
3: Thompson JL. 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. Review. PubMed PMID: 23300152.
4: Carfilzomib (Kryprolis) for multiple myeloma. Med Lett Drugs Ther. 2012 Dec 24;54(1406):103-4. Review. PubMed PMID: 23282792.
5: McCormack PL. Carfilzomib: in relapsed, or relapsed and refractory, multiple myeloma. Drugs. 2012 Oct 22;72(15):2023-32. doi: 10.2165/11209010-000000000-00000. Review. PubMed PMID: 22994535.
6: Kuhn DJ, Orlowski RZ, Bjorklund CC. Second generation proteasome inhibitors: carfilzomib and immunoproteasome-specific inhibitors (IPSIs). Curr Cancer Drug Targets. 2011 Mar;11(3):285-95. Review. PubMed PMID: 21247387.
According to Wikipedia, Carfilzomib is derived from epoxomicin, a natural product that was shown by the laboratory of Craig Crews at Yale University to inhibit the proteasome. The Crews laboratory subsequently invented a more specific derivative of epoxomicin named YU101, which was licensed to Proteolix, Inc.. Scientists at Proteolix modified YU101 to create carfilzomib, which they advanced to multiple Phase 1 and 2 clinical trials, including a pivotal Phase 2 clinical trial designed to seek accelerated approval. Clinical trials for carfilzomib continue under Onyx Pharmaceuticals, which acquired Proteolix in 2009. In January 2011, the U.S. FDA granted carfilzomib fast-track status, allowing Onyx to initiate a rolling submission of its new drug application for carfilzomib. In December 2011, the FDA granted Onyx standard review designation, for its new drug application submission based on the 003-A1 study, an open-label, single-arm Phase 2b trial. The trial evaluated 266 heavily-pretreated patients with relapsed and refractory multiple myeloma who had received at least two prior therapies, including bortezomib and either thalidomide or lenalidomide. Carfilzomib was approved by the FDA for use in patients with relapsed and refractory multiple myeloma on 20 July 2012. Onyx expects to launch the drug in the U.S. on 1 August 2012. When it launches, it will cost $10,000 per 28-day cycle, making it the most expensive FDA-approved drug for multiple myeloma. (source: http://en.wikipedia.org/wiki/Carfilzomib).
Carfilzomib is a next generation proteasome inhibitor that selectively targets the proteasome with minimal affinity for off-target proteases. To date, carfilzomib has generated a positive signal in multiple early-stage studies with an encouraging safety profile, including low rates of neuropathy, a known side effect of some approved multiple myeloma therapies. Carfilzomib primarily targets the chymotrypsin-like (CT-L) subunits in both the constitutive proteasome (c20S) and the immunoproteasome (i20S).
About epoxomicin : Epoxomicin is a naturally occurring selective proteasome inhibitor with anti-inflammatory activity. It was originally discovered in 1992. (source: http://en.wikipedia.org/wiki/Epoxomicin). Epoxomicin has the following chemical name: (2S,3S)-N-((2S,3R)-3-hydroxy-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxobutan-2-yl)-3-methyl-2-((2S,3S)-3-methyl-2-(N-methylacetamido)pentanamido)pentanamide.
epoxomicin :
Chemical Formula: C28H50N4O7
Exact Mass: 554.36795
Molecular Weight: 554.72
Elemental Analysis: C, 60.63; H, 9.09; N, 10.10; O, 20.19
Carfilzomib is an epoxomicin derivative. Structurally, carfilzomib possesses the molecular backbone of epoxomicin with 5 different substituted group (see the following graphic A, B, C, D, and E).
