U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C25H32N4O7S
Molecular Weight 532.609
Optical Activity UNSPECIFIED
Defined Stereocenters 4 / 4
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of OPROZOMIB

SMILES

COC[C@H](NC(=O)[C@H](COC)NC(=O)C1=CN=C(C)S1)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)[C@@]3(C)CO3

InChI

InChIKey=SWZXEVABPLUDIO-WSZYKNRRSA-N
InChI=1S/C25H32N4O7S/c1-15-26-11-20(37-15)24(33)29-19(13-35-4)23(32)28-18(12-34-3)22(31)27-17(21(30)25(2)14-36-25)10-16-8-6-5-7-9-16/h5-9,11,17-19H,10,12-14H2,1-4H3,(H,27,31)(H,28,32)(H,29,33)/t17-,18-,19-,25+/m0/s1

HIDE SMILES / InChI
Oprozomib (PR-047) is an orally bioavailable derivative of carfilzomib, with similar biological activity, i.e. inhibition of the chymotrypsin-like activity of the proteasome. It inhibits the activity of the proteasome, thereby blocking the targeted proteolysis normally performed by the proteasome; this may result in an accumulation of unwanted or misfolded proteins. Disruption of various cell signaling pathways may follow, eventually leading to the induction of apoptosis and inhibition of tumor growth. Oprozomib (PR-047) is being investigated for the treatment of hematologic malignancies, specifically, multiple myeloma, with Phase I/II trial ongoing.

Originator

Curator's Comment: Proteolix was acquired by Onyx Pharmaceuticals, an Amgen subsidiary, in 2009.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
82.0 nM [IC50]
Target ID: P28074|||Q86T01
Gene ID: 5693.0
Gene Symbol: PSMB5
Target Organism: Homo sapiens (Human)
36.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Doses

Doses

DosePopulationAdverse events​
330 mg 2 times / week multiple, oral
Highest studied dose
Dose: 330 mg, 2 times / week
Route: oral
Route: multiple
Dose: 330 mg, 2 times / week
Sources: Page: p.4910
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: multiple myeloma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources: Page: p.4910
DLT: Diarrhea, Hypotension...
Dose limiting toxicities:
Diarrhea (14.3%)
Hypotension (14.3%)
Sources: Page: p.4910
150 mg 1 times / day multiple, oral
MTD
Dose: 150 mg, 1 times / day
Route: oral
Route: multiple
Dose: 150 mg, 1 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: FED
Population Size: 7
Sources: Page: p.5
240 mg 1 times / day multiple, oral
MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.4910
unhealthy, ADULT
n = 8
Health Status: unhealthy
Condition: multiple myeloma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 8
Sources: Page: p.4910
DLT: Tumor lysis syndrome...
Dose limiting toxicities:
Tumor lysis syndrome (25%)
Sources: Page: p.4910
300 mg 2 times / week multiple, oral
MTD
Dose: 300 mg, 2 times / week
Route: oral
Route: multiple
Dose: 300 mg, 2 times / week
Sources: Page: p.4910
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: multiple myeloma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources: Page: p.4910
DLT: Hypotension...
Dose limiting toxicities:
Hypotension (14.3%)
Sources: Page: p.4910
90 mg 2 times / day multiple, oral
MTD
Dose: 90 mg, 2 times / day
Route: oral
Route: multiple
Dose: 90 mg, 2 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: FED
Population Size: 7
Sources: Page: p.5
DLT: Hypophosphatemia...
Dose limiting toxicities:
Hypophosphatemia (grade 3, 14.3%)
Sources: Page: p.5
180 mg 1 times / day multiple, oral
Studied dose
Dose: 180 mg, 1 times / day
Route: oral
Route: multiple
Dose: 180 mg, 1 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: FED
Population Size: 6
Sources: Page: p.5
DLT: Vomiting, Dehydration...
Dose limiting toxicities:
Vomiting (grade 3, 16.7%)
Dehydration (grade 3, 16.7%)
Hypophosphatemia (grade 3, 16.7%)
Sources: Page: p.5
210 mg 2 times / day multiple, oral (total)
Studied dose
Dose: 210 mg, 2 times / day
Route: oral
Route: multiple
Dose: 210 mg, 2 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 5
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: FED
Population Size: 5
Sources: Page: p.5
DLT: Gastrointestinal hemorrhage, Hallucinations...
Dose limiting toxicities:
Gastrointestinal hemorrhage (grade 5, 20%)
Hallucinations (grade 3, 20%)
Sources: Page: p.5
270 mg 1 times / day multiple, oral
Studied dose
Dose: 270 mg, 1 times / day
Route: oral
Route: multiple
Dose: 270 mg, 1 times / day
Sources: Page: p.4910
unhealthy, ADULT
n = 8
Health Status: unhealthy
Condition: multiple myeloma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 8
Sources: Page: p.4910
DLT: Vomiting...
Dose limiting toxicities:
Vomiting (12.5%)
Sources: Page: p.4910
AEs

AEs

AESignificanceDosePopulation
Diarrhea 14.3%
DLT
330 mg 2 times / week multiple, oral
Highest studied dose
Dose: 330 mg, 2 times / week
Route: oral
Route: multiple
Dose: 330 mg, 2 times / week
Sources: Page: p.4910
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: multiple myeloma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources: Page: p.4910
Hypotension 14.3%
DLT
330 mg 2 times / week multiple, oral
Highest studied dose
Dose: 330 mg, 2 times / week
Route: oral
Route: multiple
Dose: 330 mg, 2 times / week
Sources: Page: p.4910
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: multiple myeloma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources: Page: p.4910
Tumor lysis syndrome 25%
DLT
240 mg 1 times / day multiple, oral
MTD
Dose: 240 mg, 1 times / day
Route: oral
Route: multiple
Dose: 240 mg, 1 times / day
Sources: Page: p.4910
unhealthy, ADULT
n = 8
Health Status: unhealthy
Condition: multiple myeloma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 8
Sources: Page: p.4910
Hypotension 14.3%
DLT
300 mg 2 times / week multiple, oral
MTD
Dose: 300 mg, 2 times / week
Route: oral
Route: multiple
Dose: 300 mg, 2 times / week
Sources: Page: p.4910
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: multiple myeloma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources: Page: p.4910
Hypophosphatemia grade 3, 14.3%
DLT
90 mg 2 times / day multiple, oral
MTD
Dose: 90 mg, 2 times / day
Route: oral
Route: multiple
Dose: 90 mg, 2 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: FED
Population Size: 7
Sources: Page: p.5
Dehydration grade 3, 16.7%
DLT
180 mg 1 times / day multiple, oral
Studied dose
Dose: 180 mg, 1 times / day
Route: oral
Route: multiple
Dose: 180 mg, 1 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: FED
Population Size: 6
Sources: Page: p.5
Hypophosphatemia grade 3, 16.7%
DLT
180 mg 1 times / day multiple, oral
Studied dose
Dose: 180 mg, 1 times / day
Route: oral
Route: multiple
Dose: 180 mg, 1 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: FED
Population Size: 6
Sources: Page: p.5
Vomiting grade 3, 16.7%
DLT
180 mg 1 times / day multiple, oral
Studied dose
Dose: 180 mg, 1 times / day
Route: oral
Route: multiple
Dose: 180 mg, 1 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: FED
Population Size: 6
Sources: Page: p.5
Hallucinations grade 3, 20%
DLT
210 mg 2 times / day multiple, oral (total)
Studied dose
Dose: 210 mg, 2 times / day
Route: oral
Route: multiple
Dose: 210 mg, 2 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 5
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: FED
Population Size: 5
Sources: Page: p.5
Gastrointestinal hemorrhage grade 5, 20%
DLT, Disc. AE
210 mg 2 times / day multiple, oral (total)
Studied dose
Dose: 210 mg, 2 times / day
Route: oral
Route: multiple
Dose: 210 mg, 2 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 5
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: FED
Population Size: 5
Sources: Page: p.5
Vomiting 12.5%
DLT
270 mg 1 times / day multiple, oral
Studied dose
Dose: 270 mg, 1 times / day
Route: oral
Route: multiple
Dose: 270 mg, 1 times / day
Sources: Page: p.4910
unhealthy, ADULT
n = 8
Health Status: unhealthy
Condition: multiple myeloma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 8
Sources: Page: p.4910
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047).
2009 May 14
A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma.
2010 Dec 2
Molecular mechanisms of acquired proteasome inhibitor resistance.
2012 Dec 13
Carfilzomib and ONX 0912 inhibit cell survival and tumor growth of head and neck cancer and their activities are enhanced by suppression of Mcl-1 or autophagy.
2012 Oct 15
Patents

Sample Use Guides

Patients enrolled will receive oprozomib tablets once daily either on days 1-5 (QDx5 schedule) or on days 1, 2, 8, and 9 (QDx2 weekly schedule) of the 14-day treatment cycle.
Route of Administration: Oral
The ability of oprozomib (ONX 0912) versus carfilzomib to inhibit chymotrypsin-like (CT-L) proteasome activity using 2 different multiple myeloma (MM) cell lines. MM.1S and MM.1R were treated with ONX 0912 (3 nM) and carfilzomib (5 nM), and protein lysates were subjected to proteasome activity assays using CT-L–specific fluorogenic peptide substrates. Results showed that ONX 0912 triggers a significant and similar degree of proteasome activity inhibition as carfilzomib (P<0.05 for both cell lines).
Name Type Language
OPROZOMIB
INN   USAN   WHO-DD  
INN   USAN  
Official Name English
O-METHYL-N-((2-METHYLTHIAZOL-5-YL)CARBONYL)-L-SERYL-O-METHYL-N-((1S)-1-BENZYL-2-((2R)- 2-METHYLOXIRAN-2-YL)-2-OXOETHYL)-L-SERINAMIDE
Systematic Name English
ONX-0912
Code English
oprozomib [INN]
Common Name English
PR-047
Common Name English
ONX 0912
Code English
OPROZOMIB [USAN]
Common Name English
Oprozomib [WHO-DD]
Common Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 449614
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
FDA ORPHAN DRUG 443614
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
NCI_THESAURUS C2160
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
Code System Code Type Description
EVMPD
SUB126055
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
PRIMARY
PUBCHEM
25067547
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
PRIMARY
FDA UNII
MZ37792Y8J
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
PRIMARY
CAS
935888-69-0
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
PRIMARY
EPA CompTox
DTXSID201025950
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
PRIMARY
USAN
YY-148
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
PRIMARY
NCI_THESAURUS
C91388
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
PRIMARY
WIKIPEDIA
Oprozomib
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
PRIMARY
INN
9597
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
PRIMARY
DRUG BANK
DB11991
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
PRIMARY
SMS_ID
100000151658
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
PRIMARY
ChEMBL
CHEMBL2103884
Created by admin on Sat Dec 16 01:30:38 GMT 2023 , Edited by admin on Sat Dec 16 01:30:38 GMT 2023
PRIMARY