CARFILZOMIB

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 Search

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	No
Defined Stereocenters	5 / 5
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202714s013lbl.pdf
Curator's Comment: description was created based on several sources, including http://www.ncbi.nlm.nih.gov/pubmed/?term=23386784; http://www.ncbi.nlm.nih.gov/pubmed/?term=17591945

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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
26S proteosome 7 Target ID: CHEMBL2364701 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202714s013lbl.pdf	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Multiple myeloma 159 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202714s013lbl.pdf	Secondary		Approved 8429	KYPROLIS Approved Use Indicated in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy; as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy Launch Date 1.34274246E12

C_max

Value	Dose	Co-administered	Analyte	Population
1389 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28424963	56 mg/m² single, intravenous dose: 56 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: DEXAMETHASONE	DEXAMETHASONE	CARFILZOMIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
563 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28424963	56 mg/m² single, intravenous dose: 56 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: DEXAMETHASONE	DEXAMETHASONE	CARFILZOMIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
0.34 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28424963	56 mg/m² single, intravenous dose: 56 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: DEXAMETHASONE	DEXAMETHASONE	CARFILZOMIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
3% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf			CARFILZOMIB plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
56 mg/m2 2 times / week multiple, intravenous MTD Dose: 56 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 56 mg/m2, 2 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/27460677	unhealthy, 58 years (range:46–75 years) n = 4 Health Status: unhealthy Condition: relapsed or refractory multiple myeloma Age Group: 58 years (range:46–75 years) Sex: M+F Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/27460677	Disc. AE: Sepsis, Colon cancer... Other AEs: Lymphopenia, Thrombocytopenia... AEs leading to discontinuation/dose reduction: Sepsis (serious, 1 patient) Colon cancer (serious, 1 patient) Other AEs: Lymphopenia (grade 3-5, 75%) Thrombocytopenia (grade 3-5, 50%) Anaemia (grade 3-5, 50%) Neutropenia (grade 3-5, 50%) Pyrexia (grade 1-2, 75%) Blood creatinine increased (grade 1-2, 50%) White blood cell count increased (grade 1-2, 25%) White blood cell count decreased (grade 3-5, 25%) Nausea (grade 1-2, 50%) Stomatitis (grade 1-2, 50%) Neutrophil count increased (grade 1-2, 25%) Nasopharyngitis (grade 1-2, 25%) Vomiting (grade 1-2, 50%) C-reactive protein increased (grade 1-2, 50%) Hypophosphataemia (grade 1-2, 50%) Hypertension (grade 1-2, 50%) Malaise (grade 1-2, 25%) Aspartate aminotransferase increased (grade 1-2, 25%) Blood lactate dehydrogenase increased (grade 1-2, 25%) Haematocrit decreased (grade 1-2, 25%) Red blood cell count decreased (grade 1-2, 25%) Weight gain (grade 1-2, 25%) Sources: https://pubmed.ncbi.nlm.nih.gov/27460677
20 mg/m2 2 times / week steady, intravenous Recommended Dose: 20 mg/m2, 2 times / week Route: intravenous Route: steady Dose: 20 mg/m2, 2 times / week Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf	unhealthy, 63.0 years (range: 37- 87 years) n = 526 Health Status: unhealthy Condition: relapsed and/or refractory multiple myeloma Age Group: 63.0 years (range: 37- 87 years) Sex: M+F Population Size: 526 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf	Disc. AE: Congestive heart failure, Cardiac arrest... AEs leading to discontinuation/dose reduction: Congestive heart failure (2%) Cardiac arrest (1%) Dyspnea (1%) Blood creatinine increased (1%) Acute renal failure (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf
20 mg/m2 2 times / week steady, intravenous Recommended Dose: 20 mg/m2, 2 times / week Route: intravenous Route: steady Dose: 20 mg/m2, 2 times / week Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000MedR.pdf Page: p. 51	unhealthy, 63.0 years (range: 37- 87 years) n = 526 Health Status: unhealthy Condition: relapsed and/or refractory multiple myeloma Age Group: 63.0 years (range: 37- 87 years) Sex: M+F Population Size: 526 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000MedR.pdf Page: p. 51	Disc. AE: Pneumonia, Pyrexia... AEs leading to discontinuation/dose reduction: Pneumonia (2%) Pyrexia (1%) Thrombocytopenia (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000MedR.pdf Page: p. 51
70 mg/m2 2 times / week multiple, intravenous Highest studied dose Dose: 70 mg/m2, 2 times / week Route: intravenous Route: multiple Dose: 70 mg/m2, 2 times / week Sources: https://doi.org/10.1182/blood.V118.21.2930.2930	unhealthy, adult n = 2 Health Status: unhealthy Condition: multiple myeloma Age Group: adult Population Size: 2 Sources: https://doi.org/10.1182/blood.V118.21.2930.2930	DLT: Adverse event... Dose limiting toxicities: Adverse event Sources: https://doi.org/10.1182/blood.V118.21.2930.2930

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 substrate 1737	substrate 1037 inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A4/5 278 P-gp 1461 CYP1A2 1524 CYP2C19 1478 CYP3A 214 CYP2C8 911	peptidase 3 epoxide hydrolase 1 P-gp 1537 CYP1A2 1054 CYP2C8 693 CYP2C19 991	CYP1A2 701

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Page: 18.0	minor	yes (co-administration study) Comment: carfilzomib inhibits digoxin by 25% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Page: 18.0
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Page: 18.0	moderate [IC50 0.5 uM]	no (co-administration study) Comment: carfilzomib did not affect the cmax and auc of midazolam Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Page: 18.0
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Page: 18.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000PharmR.pdf Page: 88.0	no
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000PharmR.pdf Page: 88.0	no
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000PharmR.pdf Page: 92.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000PharmR.pdf Page: 88.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000PharmR.pdf Page: 88.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Page: 18.0	no
CYP3A 298	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000PharmR.pdf Page: 88.0	weak [IC50 3 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
epoxide hydrolase 1	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Page: 13.0	major
peptidase 3	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Page: 13.0	major
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000PharmR.pdf Page: 80.0	no
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000PharmR.pdf Page: 80.0	no
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000PharmR.pdf Page: 80.0	no
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000PharmR.pdf Page: 80.0	no
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000PharmR.pdf Page: 80.0	no
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Page: 18.0	no	no (co-administration study) Comment: carfilzomib has no effect on midazolam Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Page: 18.0
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Page: 18.0	yes	yes (co-administration study) Comment: ketoconazole decreased carfilzomib efflux ratio Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Page: 18.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202714Orig1s000SumR.pdf Page: 4.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:65347	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:65347
ChemicalBook	CB12520831	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB12520831
MolPort	MolPort-027-950-907	https://www.molport.com/shop/molecule-link/MolPort-027-950-907
Selleck Chemicals	carfilzomib-pr-171	http://www.selleckchem.com/products/carfilzomib-pr-171.html
ZINC	ZINC000049841054	http://zinc15.docking.org/substances/ZINC000049841054

PubMed

Title	Date	PubMed
Epoxomicin, a new antitumor agent of microbial origin.	1992 Nov	1468981
Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma.	2007 Nov 1	17591945
Practical considerations for multiple myeloma: an overview of recent data and current options.	2008 Aug	18952545
Mechanisms of proteasome inhibitor action and resistance in cancer.	2008 Aug-Oct	18818117
The potential of proteasome inhibitors in cancer therapy.	2008 Jun	18491989
Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma.	2008 Jun 1	18292288
Gateways to clinical trials.	2008 Mar	18560631
The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies.	2008 Oct 1	18591385
Targeting the UPS as therapy in multiple myeloma.	2008 Oct 21	19007431
The development and pharmacology of proteasome inhibitors for the management and treatment of cancer.	2009	20230760
Novel therapies for relapsed myeloma.	2009	20008242
Gateways to clinical trials.	2009 Apr	19536362
Ubiquitin Drug Discovery & Diagnostics 2009 - First Annual Conference.	2009 Dec	19943215
Discovery of novel proteasome inhibitors using a high-content cell-based screening system.	2009 Dec 30	20041034
Clinical development of novel proteasome inhibitors for cancer treatment.	2009 Jul	19505187
New drugs in multiple myeloma and the significance of autologous stem cell transplants.	2009 Mar	19398940
Antiproliferative and proapoptotic effects of proteasome inhibitors and their combination with histone deacetylase inhibitors on leukemia cells.	2009 Mar	19275578
Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047).	2009 May 14	19348473
Gateways to clinical trials.	2009 Nov	20094643
Proteasome inhibitors in the treatment of multiple myeloma.	2009 Nov	19741722
Acquisition of a multidrug-resistant phenotype with a proteasome inhibitor in multiple myeloma.	2009 Nov	19516276
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	19903785
Future novel single agent and combination therapies.	2009 Nov-Dec	20010171
Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome.	2009 Oct 15	19671918
State-of-the-Art Management of Complications of Myeloma and Its Treatment.	2010	20671999
Proteasome inhibitors: recent advances and new perspectives in medicinal chemistry.	2010	20166955
Bortezomib.	2010	20072838
New twists on proteasome inhibitors.	2010 Dec	21139600
Targeting histone deacetyalses in the treatment of B- and T-cell malignancies.	2010 Dec	21132350
Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70.	2010 Jan	20066033
Peripheral neuropathy during bortezomib treatment of multiple myeloma: a review of recent studies.	2010 Jul	20497001
Lenalidomide in multiple myeloma: an evidence-based review of its role in therapy.	2010 Jun 15	20694078
The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo.	2010 Jun 3	20233973
Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S beta5-subunit.	2010 Sep 15	20632995
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	21685914
Carfilzomib.	2013 Feb 7	23393020
Possible role of selective, irreversible, proteasome inhibitor (carfilzomib) in the treatment of rat hepatocellular carcinoma.	2014 May 25	24632418

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 `Fri Dec 15 15:54:47 UTC 2023` Edited by `admin` on `Fri Dec 15 15:54:47 UTC 2023`
Record UNII	72X6E3J5AR
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

CARFILZOMIB

Official Name

English

CARFILZOMIB [ORANGE BOOK]

Common Name

English

PR-171

Code

English

NSC-758252

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

Carfilzomib [WHO-DD]

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 [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

FDA ORPHAN DRUG

795120