Carfilzomib
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    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.


Chemical Structure

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Carfilzomib
CAS# 868540-17-4

Theoretical Analysis

MedKoo Cat#: 200630
Name: Carfilzomib
CAS#: 868540-17-4
Chemical Formula: C40H57N5O7
Exact Mass: 719.43
Molecular Weight: 719.910
Elemental Analysis: C, 66.73; H, 7.98; N, 9.73; O, 15.56

Price and Availability

Size Price Availability Quantity
25mg USD 90 Ready to ship
50mg USD 150 Ready to ship
100mg USD 250 Ready to ship
200mg USD 450 Ready to ship
500mg USD 950 Ready to ship
600mg USD 1140 Ready to ship
1g USD 1650 Ready to ship
2g USD 2950 Ready to ship
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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

More Info: 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).        

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

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 59.3 82.30
DMF 57.5 79.87
Ethanol 7.7 10.70

Preparing Stock Solutions

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.

Recalculate based on batch purity %
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.

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1: Moreau P, Dimopoulos MA, Mikhael J, Yong K, Capra M, Facon T, Hajek R, Špička I, Baker R, Kim K, Martinez G, Min CK, Pour L, Leleu X, Oriol A, Koh Y, Suzuki K, Risse ML, Asset G, Macé S, Martin T; IKEMA study group. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021 Jun 19;397(10292):2361-2371. doi: 10.1016/S0140-6736(21)00592-4. Epub 2021 Jun 4. PMID: 34097854.


2: Dimopoulos M, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, Weisel K, Yang H, Klippel Z, Zahlten-Kumeli A, Usmani SZ. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020 Jul 18;396(10245):186-197. doi: 10.1016/S0140-6736(20)30734-0. Erratum in: Lancet. 2020 Aug 15;396(10249):466. PMID: 32682484.


3: Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. doi: 10.1056/NEJMoa1411321. Epub 2014 Dec 6. PMID: 25482145.


4: Gay F, Musto P, Rota-Scalabrini D, Bertamini L, Belotti A, Galli M, Offidani M, Zamagni E, Ledda A, Grasso M, Ballanti S, Spadano A, Cea M, Patriarca F, D'Agostino M, Capra A, Giuliani N, de Fabritiis P, Aquino S, Palmas A, Gamberi B, Zambello R, Petrucci MT, Corradini P, Cavo M, Boccadoro M. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open- label, phase 2 trial. Lancet Oncol. 2021 Dec;22(12):1705-1720. doi: 10.1016/S1470-2045(21)00535-0. Epub 2021 Nov 11. PMID: 34774221.


5: Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR Investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. doi: 10.1016/S1470-2045(15)00464-7. Epub 2015 Dec 5. PMID: 26671818.


6: Zhou Q, Liang J, Yang T, Liu J, Li B, Li Y, Fan Z, Wang W, Chen W, Yuan S, Xu M, Xu Q, Luan Z, Xia Z, Zhou P, Huang Y, Chen L. Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer. EMBO Mol Med. 2022 Jan 11;14(1):e14502. doi: 10.15252/emmm.202114502. Epub 2021 Dec 13. PMID: 34898004; PMCID: PMC8749493.


7: Chari A, Martinez-Lopez J, Mateos MV, Bladé J, Benboubker L, Oriol A, Arnulf B, Rodriguez-Otero P, Pineiro L, Jakubowiak A, de Boer C, Wang J, Clemens PL, Ukropec J, Schecter J, Lonial S, Moreau P. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2019 Aug 1;134(5):421-431. doi: 10.1182/blood.2019000722. Epub 2019 May 21. PMID: 31113777; PMCID: PMC6676132.


8: Kortuem KM, Stewart AK. Carfilzomib. Blood. 2013 Feb 7;121(6):893-7. doi: 10.1182/blood-2012-10-459883. PMID: 23393020.


9: Gasparetto C, Schiller GJ, Tuchman SA, Callander NS, Baljevic M, Lentzsch S, Rossi AC, Kotb R, White D, Bahlis NJ, Chen CI, Sutherland HJ, Madan S, LeBlanc R, Sebag M, Venner CP, Bensinger WI, Biran N, Ammu S, Ben-Shahar O, DeCastro A, Van Domelen D, Zhou T, Zhang C, Bentur OS, Shah J, Shacham S, Kauffman M, Lipe B. Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non- refractory multiple myeloma patients. Br J Cancer. 2022 Mar;126(5):718-725. doi: 10.1038/s41416-021-01608-2. Epub 2021 Nov 20. PMID: 34802051; PMCID: PMC8605887.


10: Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015 Nov 12;126(20):2284-90. doi: 10.1182/blood-2015-05-643320. Epub 2015 Sep 17. PMID: 26384354; PMCID: PMC4643003.


11: Moreau P, Dimopoulos MA, Yong K, Mikhael J, Risse ML, Asset G, Martin T. Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design. Future Oncol. 2020 Jan;16(2):4347-4358. doi: 10.2217/fon-2019-0431. Epub 2019 Dec 13. PMID: 31833394.


12: Touzeau C, Antier C, Moreau P. Carfilzomib in combination with daratumumab in the management of relapsed multiple myeloma. Future Oncol. 2021 Mar;17(9):993-998. doi: 10.2217/fon-2020-0907. Epub 2020 Dec 8. PMID: 33289427.


13: Andreu-Vieyra C, Berenson JR. Carfilzomib in multiple myeloma. Expert Opin Biol Ther. 2014 Nov;14(11):1685-99. doi: 10.1517/14712598.2014.953050. Epub 2014 Aug 29. PMID: 25170966.


14: Costa LJ, Davies FE, Monohan GP, Kovacsovics T, Burwick N, Jakubowiak A, Kaufman JL, Hong WJ, Dail M, Salem AH, Yang X, Masud AA, Munasinghe W, Ross JA, Bueno OF, Kumar SK, Stadtmauer EA. Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Blood Adv. 2021 Oct 12;5(19):3748-3759. doi: 10.1182/bloodadvances.2020004146. PMID: 34470049; PMCID: PMC8679663.


15: Capra M, Martin T, Moreau P, Baker R, Pour L, Min CK, Leleu X, Mohty M, Segura MR, Turgut M, LeBlanc R, Risse ML, Malinge L, Schwab S, Dimopoulos M. Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in relapsed multiple myeloma patients with renal impairment: IKEMA subgroup analysis. Haematologica. 2022 Jun 1;107(6):1397-1409. doi: 10.3324/haematol.2021.279229. PMID: 34647444; PMCID: PMC9152981.


16: Engelhardt M, Szymaniak-Vits M, Ajayi S, Dold SM, Müller SJ, Scheubeck S, Wäsch R. Carfilzomib. Recent Results Cancer Res. 2018;212:265-283. doi: 10.1007/978-3-319-91439-8_13. PMID: 30069635.


17: Landgren O, Sonneveld P, Jakubowiak A, Mohty M, Iskander KS, Mezzi K, Siegel DS. Carfilzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma. Leukemia. 2019 Sep;33(9):2127-2143. doi: 10.1038/s41375-019-0517-6. Epub 2019 Jul 24. PMID: 31341235; PMCID: PMC6756042.


18: Moreau P, Mateos MV, Berenson JR, Weisel K, Lazzaro A, Song K, Dimopoulos MA, Huang M, Zahlten-Kumeli A, Stewart AK. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018 Jul;19(7):953-964. doi: 10.1016/S1470-2045(18)30354-1. Epub 2018 Jun 1. Erratum in: Lancet Oncol. 2018 Aug;19(8):e382. PMID: 29866475.


19: Dytfeld D, Wróbel T, Jamroziak K, Kubicki T, Robak P, Walter-Croneck A, Czyż J, Tyczyńska A, Druzd-Sitek A, Giannopoulos K, Nowicki A, Szczepaniak T, Łojko- Dankowska A, Matuszak M, Gil L, Puła B, Rybka J, Majcherek M, Usnarska- Zubkiewicz L, Szukalski Ł, Końska A, Zaucha JM, Walewski J, Mikulski D, Czabak O, Robak T, Lahoud OB, Zonder JA, Griffith K, Stefka A, Major A, Derman BA, Jakubowiak AJ. Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open- label, phase 3 trial. Lancet Oncol. 2023 Feb;24(2):139-150. doi: 10.1016/S1470-2045(22)00738-0. Epub 2023 Jan 12. PMID: 36642080; PMCID: PMC10337122.


20: Pennipede D, Mohyuddin GR, Hawkins R, Ganguly S, Shune L, Ahmed N, Mohan M, Cui W, Mahmoudjafari Z, McGuirk J, Atrash S, Abdallah AO. Carfilzomib, cyclophosphamide, and dexamethasone (KCd) for the treatment of triple-class relapsed/refractory multiple myeloma (RRMM). Eur J Haematol. 2021 Dec;107(6):602-608. doi: 10.1111/ejh.13697. Epub 2021 Aug 31. PMID: 34378251.

This product was cited in below publications.
1. Okabe S, Tanaka Y, Gotoh A. Targeting phosphoinositide 3-kinases and histone deacetylases in multiple myeloma. Exp Hematol Oncol. 2021 Mar 4;10(1):19. doi: 10.1186/s40164-021-00213-6. PMID: 33663586; PMCID: PMC7934550.