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Details

Stereochemistry ABSOLUTE
Molecular Formula C40H57N5O7
Molecular Weight 719.9099
Optical Activity UNSPECIFIED
Defined Stereocenters 5 / 5
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of CARFILZOMIB

SMILES

CC(C)C[C@H](NC(=O)[C@H](CCC1=CC=CC=C1)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC3=CC=CC=C3)C(=O)N[C@@H](CC(C)C)C(=O)[C@@]4(C)CO4

InChI

InChIKey=BLMPQMFVWMYDKT-NZTKNTHTSA-N
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

HIDE SMILES / InChI

Molecular Formula C40H57N5O7
Molecular Weight 719.9099
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry
Defined Stereocenters 5 / 5
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

Carfilzomib is an epoxomicin derivate with potential antineoplastic activity. Kyprolis (carfilzomib's trade name) is a proteasome inhibitor that is indicated for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy as a single agent or in combination with dexamethasone or with lenalidomide plus dexamethasone. Carfilzomib is made up of four modified peptides. It 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. 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.

CNS Activity

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Conditions
PubMed

PubMed

TitleDatePubMed
Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma.
2007 Nov 1
Practical considerations for multiple myeloma: an overview of recent data and current options.
2008 Aug
Mechanisms of proteasome inhibitor action and resistance in cancer.
2008 Aug-Oct
The potential of proteasome inhibitors in cancer therapy.
2008 Jun
The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies.
2008 Oct 1
Gateways to clinical trials.
2009 Apr
Clinical development of novel proteasome inhibitors for cancer treatment.
2009 Jul
A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies.
2009 Nov 15
Relapsed multiple myeloma.
2010
State-of-the-Art Management of Complications of Myeloma and Its Treatment.
2010
Bortezomib.
2010
Novel disease targets and management approaches for diffuse large B-cell lymphoma.
2010 Aug
New twists on proteasome inhibitors.
2010 Dec
Targeting histone deacetyalses in the treatment of B- and T-cell malignancies.
2010 Dec
Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70.
2010 Jan
Lenalidomide in multiple myeloma: an evidence-based review of its role in therapy.
2010 Jun 15
Proteasome inhibition and its therapeutic potential in multiple myeloma.
2010 Sep 28
A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation.
2011 Jun 19
Carfilzomib.
2013 Feb 7
Possible role of selective, irreversible, proteasome inhibitor (carfilzomib) in the treatment of rat hepatocellular carcinoma.
2014 May 25
Patents

Sample Use Guides

In Vivo Use Guide
For monotherapy, administer Kyprolis intravenously as a 10-minute or 30-minute infusion depending on the regimen as described: for monotherapy using the 20/27 mg/m^2 regimen, administer Kyprolis intravenously as a 10-minute infusion. In Cycles 1 through 12, administer Kyprolis on two consecutive days, each week for three weeks followed by a 12-day rest period. Each 28-day period is considered one treatment cycle. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis. The recommended starting dose of Kyprolis is 20 mg/m^2 in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 27 mg/m^2 on Day 8 of Cycle 1. Treatment may continue until disease progression or unacceptable toxicity occurs. For the combination regimen with lenalidomide and dexamethasone, administer Kyprolis intravenously as a 10-minute infusion on two consecutive days, each week for three weeks followed by a 12-day rest period. Each 28-day period is considered one treatment cycle. The recommended starting dose of Kyprolis is 20 mg/m^2 in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 27 mg/m^2 on Day 8 of Cycle 1. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis. Discontinue Kyprolis after Cycle 18. Lenalidomide 25 mg is taken orally on Days 1–21 and dexamethasone 40 mg by mouth or intravenously on days 1, 8, 15, and 22 of the 28-day cycles. Continue treatment until disease progression or unacceptable toxicity occurs.
Route of Administration: Intravenous
In Vitro Use Guide
To determine whether JNK activation is important in mediating carfilzomib-induced apoptosis, RPMI 8226 cells were exposed to a pulse of 100 nM carfilzomib
Substance Class Chemical
Created
by admin
on Mon Oct 21 20:56:20 UTC 2019
Edited
by admin
on Mon Oct 21 20:56:20 UTC 2019
Record UNII
72X6E3J5AR
Record Status Validated (UNII)
Record Version
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Name Type Language
CARFILZOMIB
DASH   INN   MI   ORANGE BOOK   USAN   VANDF   WHO-DD  
USAN   INN  
Official Name English
CARFILZOMIB [ORANGE BOOK]
Common Name English
PR-171
Code English
L-PHENYLALANINAMIDE, (.ALPHA.S)-.ALPHA.-((4-MORPHOLINYLACETYL)AMINO)BENZENEBUTANOYL-L-LEUCYL-N-((1S)-3-METHYL-1-(((2R)-2-METHYLOXIRANYL)CARBONYL)BUTYL)-
Common Name English
(2S)-N-((1S)-1-BENZYL-2-(((1S)-3-METHYL-1-(((2R)-2-METHYLOXIRAN-2-YL)CARBONYL)BUTYL)AMINO)-2-OXOETHYL)-4-METHYL-2-(((2S)-2-((MORPHOLIN-4-YLACETYL)AMINO)-4-PHENYLBUTANOYL)AMINO)PENTANAMIDE
Common Name English
KYPROLIS
Brand Name English
CARFILZOMIB [WHO-DD]
Common Name English
CARFILZOMIB [MI]
Common Name English
CARFILZOMIB [USAN]
Common Name English
CARFILZOMIB [VANDF]
Common Name English
CARFILZOMIB [JAN]
Common Name English
CARFILZOMIB [INN]
Common Name English
Classification Tree Code System Code
NDF-RT N0000175604
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
FDA ORPHAN DRUG 252507
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
WHO-VATC QL01XX45
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
EMA ASSESSMENT REPORTS KYPROLIS (AUTHORIZED: MULTIPLE MYELOMA)
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
EU-Orphan Drug EU/3/08/548
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
WHO-ATC L01XX45
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
NCI_THESAURUS C2160
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
Code System Code Type Description
NCI_THESAURUS
C52196
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY
WIKIPEDIA
Carfilzomib
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY
INN
8859
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY
CAS
868540-17-4
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY
MESH
C524865
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY
MERCK INDEX
M3107
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY Merck Index
DRUG BANK
DB08889
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY
LactMed
868540-17-4
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY
RXCUI
1302966
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY RxNorm
EVMPD
SUB32911
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY
EPA CompTox
868540-17-4
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY
IUPHAR
7420
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY
ChEMBL
CHEMBL451887
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY
PUBCHEM
11556711
Created by admin on Mon Oct 21 20:56:20 UTC 2019 , Edited by admin on Mon Oct 21 20:56:20 UTC 2019
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
TRANSPORTER -> SUBSTRATE
METABOLIC ENZYME -> INHIBITOR
IC50
TRANSPORTER -> INHIBITOR
WEAK
TARGET -> INHIBITOR
TARGET -> INHIBITOR
METABOLIC ENZYME -> INHIBITOR
IC50
TARGET -> INHIBITOR
TARGET -> INHIBITOR
TARGET -> INHIBITOR
BINDER->LIGAND
BINDING
Related Record Type Details
METABOLITE -> PARENT
MAJOR
PLASMA; URINE
METABOLITE INACTIVE -> PARENT
Cytochrome P450-mediated mechanisms played a minor role in overall carfilzomib metabolism
MAJOR
PLASMA
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC
Biological Half-life PHARMACOKINETIC