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MedKoo CAT#: 200630
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 (PR171)
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.
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.
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).
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.