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Identification
NameCarfilzomib
Accession NumberDB08889
TypeSmall Molecule
GroupsApproved
Description

Carfilzomib is an injectable antineoplastic agent (IV only). Chemically, it is a modified tetrapeptidyl epoxide and an analog of epoxomicin. It is also a selective proteasome inhibitor. FDA approved on July 20, 2012.

Structure
Thumb
Synonyms
Kyprolis
PR-171
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Kyprolisinjection, powder, lyophilized, for solution60 mg/30mLintravenousOnyx Pharmaceuticals, Inc.2012-07-20Not applicableUs
Kyprolispowder for solution60 mgintravenousAmgen Canada Inc2016-02-11Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII72X6E3J5AR
CAS number868540-17-4
WeightAverage: 719.9099
Monoisotopic: 719.425799203
Chemical FormulaC40H57N5O7
InChI KeyInChIKey=BLMPQMFVWMYDKT-NZTKNTHTSA-N
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
IUPAC Name
(2S)-4-methyl-N-[(1S)-1-{[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]carbamoyl}-2-phenylethyl]-2-[(2S)-2-[2-(morpholin-4-yl)acetamido]-4-phenylbutanamido]pentanamide
SMILES
CC(C)C[[email protected]](NC(=O)[[email protected]](CCC1=CC=CC=C1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)[C@@]1(C)CO1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as peptides. These are compounds containing an amide derived from two or more amino carboxylic acid molecules (the same or different) by formation of a covalent bond from the carbonyl carbon of one to the nitrogen atom of another.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentPeptides
Alternative Parents
Substituents
  • Alpha peptide
  • N-acyl-alpha amino acid or derivatives
  • Alpha-amino acid amide
  • Phenylpropylamine
  • Amphetamine or derivatives
  • Alpha-amino acid or derivatives
  • N-substituted-alpha-amino acid
  • Fatty acyl
  • Benzenoid
  • Oxazinane
  • N-acyl-amine
  • Morpholine
  • Fatty amide
  • Monocyclic benzene moiety
  • Alpha-aminoketone
  • Tertiary aliphatic amine
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Ketone
  • Carboxamide group
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Ether
  • Oxirane
  • Dialkyl ether
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationCarfilzomib is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate.
PharmacodynamicsIntravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like activity when measured in blood 1 hour after the first dose. On Day 1 of Cycle 1, proteasome inhibition in peripheral blood mononuclear cells (PBMCs) ranged from 79% to 89% at 15 mg/m2, and from 82% to 83% at 20 mg/m2. In addition, carfilzomib administration resulted in inhibition of the LMP2 and MECL1 subunits of the immunoproteasome ranging from 26% to 32% and 41% to 49%, respectively, at 20 mg/m2. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing. Resistance against carfilzomib has been observed and although the mechanism has not been confirmed, it is thought that up-regulation of P-glycoprotein may be a contributing factor. Furthermore, studies suggest that carfilzomib is more potent than bortezomib.
Mechanism of actionCarfilzomib is made up of four modified peptides and acts as a proteasome inhibitor. Carfilzomib irreversibly and selectively binds to N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. This 20S core has 3 catalytic active sites: the chymotrypsin, trypsin, and caspase-like sites. Inhibition of the chymotrypsin-like site by carfilzomib (β5 and β5i subunits) is the most effective target in decreasing cellular proliferation, ultimately resulting in cell cycle arrest and apoptosis of cancerous cells. At higher doses, carfilzomib will inhibit the trypsin-and capase-like sites.
Related Articles
AbsorptionCmax, single IV dose of 27 mg/m^2 = 4232 ng/mL; AUC, single IV dose of 27 mg/m^2 = 379 ng•hr/mL; Carfilzomib does not accumulation in the systemic. At doses between 20 and 36 mg/m2, there was a dose-dependent increase in exposure.
Volume of distribution

Vd, steady state, 20 mg/m^2 = 28 L

Protein bindingOver the concentration range of 0.4 - 4 micromolar, carfilzomib was 97% protein bound.
Metabolism

Carfilzomib was rapidly and extensively metabolized by the liver. The predominant metabolites were the peptide fragments and the diol of carfilzomib which suggests that the main metabolic pathways are peptidase cleavage and epoxide hydrolysis. The cytochrome P450 enzyme system is minimally involved in the metabolism of carfilzomib. All metabolites are inactive.

Route of eliminationNot Available
Half lifeFollowing intravenous administration of doses ≥ 15 mg/m^2, carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1.
Clearance

Systemic clearance = 151 – 263 L/hour. As this value exceeds hepatic blood flow, it suggests that carfilozmib is cleared extrahepatically.

ToxicityMost commonly reported adverse reactions (incidence ≥ 30%) are fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. The two dose limiting toxicities are thrombocytopenia and febrile neutropenia. Maximum tolerate dose = 15 mg/m^2
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.7982
Blood Brain Barrier-0.8941
Caco-2 permeable-0.6924
P-glycoprotein substrateSubstrate0.9378
P-glycoprotein inhibitor IInhibitor0.8224
P-glycoprotein inhibitor IINon-inhibitor0.9045
Renal organic cation transporterNon-inhibitor0.8642
CYP450 2C9 substrateNon-substrate0.8812
CYP450 2D6 substrateNon-substrate0.7587
CYP450 3A4 substrateSubstrate0.6641
CYP450 1A2 substrateNon-inhibitor0.9031
CYP450 2C9 inhibitorNon-inhibitor0.8546
CYP450 2D6 inhibitorNon-inhibitor0.7152
CYP450 2C19 inhibitorNon-inhibitor0.6665
CYP450 3A4 inhibitorInhibitor0.6532
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9676
Ames testNon AMES toxic0.7119
CarcinogenicityNon-carcinogens0.8431
BiodegradationNot ready biodegradable0.9942
Rat acute toxicity2.6381 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9831
hERG inhibition (predictor II)Non-inhibitor0.6044
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionintravenous60 mg/30mL
Powder for solutionintravenous60 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7232818 No2005-04-142025-04-14Us
US7417042 No2006-06-072026-06-07Us
US7491704 No2005-04-142025-04-14Us
US7737112 No2007-12-072027-12-07Us
US8129346 No2006-12-252026-12-25Us
US8207125 No2005-04-142025-04-14Us
US8207126 No2005-04-142025-04-14Us
US8207127 No2005-04-142025-04-14Us
US8207297 No2005-04-142025-04-14Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilityInsoluble FDA
pKa3.5FDA
Predicted Properties
PropertyValueSource
Water Solubility0.00484 mg/mLALOGPS
logP3.21ALOGPS
logP4.2ChemAxon
logS-5.2ALOGPS
pKa (Strongest Acidic)11.91ChemAxon
pKa (Strongest Basic)4.96ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area158.47 Å2ChemAxon
Rotatable Bond Count20ChemAxon
Refractivity198.02 m3·mol-1ChemAxon
Polarizability79.44 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis ReferenceNot Available
General References
  1. Kortuem KM, Stewart AK: Carfilzomib. Blood. 2013 Feb 7;121(6):893-7. doi: 10.1182/blood-2012-10-459883. [PubMed:23393020 ]
  2. 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:17591945 ]
External Links
ATC CodesL01XX45
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (310 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
ClozapineThe risk or severity of adverse effects can be increased when Carfilzomib is combined with Clozapine.
LumacaftorThe serum concentration of Carfilzomib can be decreased when it is combined with Lumacaftor.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Carfilzomib.
RanolazineThe serum concentration of Carfilzomib can be increased when it is combined with Ranolazine.
SaquinavirThe serum concentration of Carfilzomib can be increased when it is combined with Saquinavir.
TesmilifeneThe serum concentration of Carfilzomib can be decreased when it is combined with Tesmilifene.
VerapamilThe serum concentration of Carfilzomib can be increased when it is combined with Verapamil.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Threonine-type endopeptidase activity
Specific Function:
The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This unit is responsible of the chymotrypsin-like activity of the proteasome and is one of the principal target of the proteasome in...
Gene Name:
PSMB5
Uniprot ID:
P28074
Molecular Weight:
28480.01 Da
References
  1. Kortuem KM, Stewart AK: Carfilzomib. Blood. 2013 Feb 7;121(6):893-7. doi: 10.1182/blood-2012-10-459883. [PubMed:23393020 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Threonine-type endopeptidase activity
Specific Function:
The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB5 by PSMB8 increases the cap...
Gene Name:
PSMB8
Uniprot ID:
P28062
Molecular Weight:
30354.035 Da
References
  1. 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:17591945 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Threonine-type endopeptidase activity
Specific Function:
The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity.
Gene Name:
PSMB1
Uniprot ID:
P20618
Molecular Weight:
26489.09 Da
References
  1. 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:17591945 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Threonine-type endopeptidase activity
Specific Function:
The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB6 by PSMB9 increases the cap...
Gene Name:
PSMB9
Uniprot ID:
P28065
Molecular Weight:
23264.1 Da
References
  1. 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:17591945 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Threonine-type endopeptidase activity
Specific Function:
The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit has a trypsin-like activity.
Gene Name:
PSMB2
Uniprot ID:
P49721
Molecular Weight:
22836.02 Da
References
  1. 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:17591945 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Threonine-type endopeptidase activity
Specific Function:
The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides.
Gene Name:
PSMB10
Uniprot ID:
P40306
Molecular Weight:
28936.08 Da
References
  1. 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:17591945 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
Comments
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Drug created on May 29, 2013 16:03 / Updated on August 24, 2016 01:52