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Carfilzomib

Description of Carfilzomib:  Carfilzomib, a tetrapeptide epoxyketone, is 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. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer: Oynx Pharmaceuticals/Proteolix Inc

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.

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).

Highlight of recent study using carfilzomib

Carfilzomib clinical trials in multiple myeloma patients. The ubiquitin-proteasome pathway regulates bone formation through osteoblast differentiation. We analyzed variation Alkaline Phosphatase (ALP) during carfilzomib treatment. Data from 38 patients enrolled in the PX-171-003 and 29 patients in PX-171-004 studies, for relapsed/refractory myeloma patients, were analyzed. All patients received 20 mg/m(2) of carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Sixty seven patients from ALP data were evaluable. In PX-171-003 the ORR (>PR) was 18% and the clinical benefit response (CBR; >MR) was 26%, while in PX-171-004 the ORR was 35.5% overall and 57% in bortezomib naive patients. ALP increment from baseline was statistically different in patients who achieved ≥VGPR compared to all others on Days 1 (P=0.0049) and 8 (P=0.006) of Cycle 2. In patients achieving a VGPR or better, ALP increased more than 15 units per liter at Cycle 2 Day 1 over baseline. An ALP increase over the same period of time was seen in 26%, 13%, and 11% of patients achieving PR, MR, and SD, respectively. This retrospective analysis of relapsed or refractory myeloma patients treated with single agent carfilzomib indicates that early elevation in ALP is associated with subsequent myeloma response. [source: Eur J Haematol. 2011 Jun;86(6):484-487.) 

Carfilzomib's activity: In preclinical studies, carfilzomib demonstrated irreversible binding to the proteasome and minimal off-target inhibition of other proteases. In clinical studies carfilzomib has demonstrated substantial antitumor activity in hematologic malignancies while exhibiting a well-tolerated side-effect profile. Painful neuropathy was minimally reported, suggesting a possible advantage over other proteasome inhibitors. With single-agent carfilzomib, dose-limiting toxicity was hematologic and included thrombocytopenia and neutropenia. In patients with relapsed or refractory multiple myeloma, twice-weekly consecutive-day single-agent carfilzomib 20 mg/m(2) for 3 weeks every 28 days, escalating to 27 mg/m(2) the second cycle was associated with a 54% overall response rate in bortezomib-naive patients and a 26% overall response rate in bortezomib and immunomodulatory drug refractory patients.(source: Future Oncol. 2011 May;7(5):607-12.).

1: Yang J, Wang Z, Fang Y, Jiang J, Zhao F, Wong H, Bennett MK, Molineaux CJ, Kirk CJ. Pharmacokinetics, pharmacodynamics, metabolism, distribution, and excretion of carfilzomib in rats. Drug Metab Dispos. 2011 Oct;39(10):1873-82. Epub 2011 Jul 13. PubMed PMID: 21752943.

2: Dasmahapatra G, Lembersky D, Son MP, Attkisson E, Dent P, Fisher RI, Friedberg JW, Grant S. Carfilzomib interacts synergistically with histone deacetylase inhibitors in mantle cell lymphoma cells in vitro and in vivo. Mol Cancer Ther. 2011 Sep;10(9):1686-97. Epub 2011 Jul 12. PubMed PMID: 21750224; PubMed Central PMCID: PMC3170445.

3: Jain S, Diefenbach C, Zain J, O'Connor OA. Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma. Core Evid. 2011;6:43-57. Epub 2011 Apr 4. PubMed PMID: 21654882; PubMed Central PMCID: PMC3102580.

4: Mirabella AC, Pletnev AA, Downey SL, Florea BI, Shabaneh TB, Britton M, Verdoes M, Filippov DV, Overkleeft HS, Kisselev AF. Specific cell-permeable inhibitor of proteasome trypsin-like sites selectively sensitizes myeloma cells to bortezomib and carfilzomib. Chem Biol. 2011 May 27;18(5):608-18. doi: 0.1016/j.chembiol.2011.02.015. PubMed PMID: 21609842; PubMed Central PMCID: PMC3134264.

5: Khan ML, Stewart AK. Carfilzomib: a novel second-generation proteasome inhibitor. Future Oncol. 2011 May;7(5):607-12. PubMed PMID: 21568676.

6: Zangari M, Aujay M, Zhan F, Hetherington KL, Berno T, Vij R, Jagannath S, Siegel D, Keith Stewart A, Wang L, Orlowski RZ, Belch A, Jakubowiak A, Somlo G, Trudel S, Bahlis N, Lonial S, Singhal S, Kukreti V, Tricot G. Alkaline phosphatase variation during carfilzomib treatment is associated with best response in multiple myeloma patients. Eur J Haematol. 2011 Jun;86(6):484-7. doi: 10.1111/j.1600-0609.2011.01602.x. PubMed PMID: 21477075.

7: Arastu-Kapur S, Anderl JL, Kraus M, Parlati F, Shenk KD, Lee SJ, Muchamuel T, Bennett MK, Driessen C, Ball AJ, Kirk CJ. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res. 2011 May 1;17(9):2734-43. Epub 2011 Mar 1. PubMed PMID: 21364033.

8: Sacco A, Aujay M, Morgan B, Azab AK, Maiso P, Liu Y, Zhang Y, Azab F, Ngo HT, Issa GC, Quang P, Roccaro AM, Ghobrial IM. Carfilzomib-dependent selective inhibition of the chymotrypsin-like activity of the proteasome leads to antitumor activity in Waldenstrom's Macroglobulinemia. Clin Cancer Res. 2011 Apr 1;17(7):1753-64. Epub 2011 Feb 25. PubMed PMID: 21355079.

9: J Kuhn D, Z Orlowski R, C Bjorklund C. Second generation proteasome inhibitors: carfilzomib and immunoproteasome-specific inhibitors (IPSIs). Curr Cancer Drug Targets. 2011 Mar;11(3):285-95. Review. PubMed PMID: 21247387.

10: Dasmahapatra G, Lembersky D, Kramer L, Fisher RI, Friedberg J, Dent P, Grant S. The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. Blood. 2010 Jun 3;115(22):4478-87. Epub 2010 Mar 16. PubMed PMID: 20233973; PubMed Central PMCID: PMC2881506.

11: O'Connor OA, Stewart AK, Vallone M, Molineaux CJ, Kunkel LA, Gerecitano JF, Orlowski RZ. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res. 2009 Nov 15;15(22):7085-91. Epub 2009 Nov 10. PubMed PMID: 19903785.

12: Parlati F, Lee SJ, Aujay M, Suzuki E, Levitsky K, Lorens JB, Micklem DR, Ruurs P, Sylvain C, Lu Y, Shenk KD, Bennett MK. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood. 2009 Oct 15;114(16):3439-47. Epub 2009 Aug 11. PubMed PMID: 19671918.

13: Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM, Demo SD, Bennett MK, van Leeuwen FW, Chanan-Khan AA, Orlowski RZ. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007 Nov 1;110(9):3281-90. Epub 2007 Jun 25. PubMed PMID: 17591945; PubMed Central PMCID: PMC2200918.