OPROZOMIB

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 Search

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

Description
Sources: https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=674605 | https://www.ncbi.nlm.nih.gov/pubmed/19348473

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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Proteasome subunit beta type-8 3 Target ID: CHEMBL5620 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19348473	Inhibitor 8297		82.0 nM [IC50]
Proteasome subunit beta type-5 6 Target ID: P28074\|\|\|Q86T01 Gene ID: 5693.0 Gene Symbol: PSMB5 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/19348473	Inhibitor 8297		36.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Multiple myeloma 159 Sources: https://clinicaltrials.gov/ct2/show/study/NCT01416428	Primary	Phase II 1132	Unknown Approved Use Unknown
Waldenström's macroglobulinemia 7 Sources: https://clinicaltrials.gov/ct2/show/study/NCT01416428	Primary	Phase II 1132	Unknown Approved Use Unknown
Hepatocellular carcinoma 83 Sources: https://clinicaltrials.gov/ct2/show/NCT02227914	Primary	Phase II 1132	Unknown Approved Use Unknown

Doses

Dose	Population	Adverse 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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 Page: p.4910	DLT: Diarrhea, Hypotension... Dose limiting toxicities: Diarrhea (14.3%) Hypotension (14.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 Page: p.5	Sources: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 Page: p.4910	DLT: Tumor lysis syndrome... Dose limiting toxicities: Tumor lysis syndrome (25%) Sources: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 Page: p.4910	DLT: Hypotension... Dose limiting toxicities: Hypotension (14.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 Page: p.5	DLT: Hypophosphatemia... Dose limiting toxicities: Hypophosphatemia (grade 3, 14.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 Page: p.5	DLT: Gastrointestinal hemorrhage, Hallucinations... Dose limiting toxicities: Gastrointestinal hemorrhage (grade 5, 20%) Hallucinations (grade 3, 20%) Sources: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 Page: p.4910	DLT: Vomiting... Dose limiting toxicities: Vomiting (12.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/31142508 Page: p.4910

AEs

AE	Significance	Dose	Population
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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/26924128 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: https://pubmed.ncbi.nlm.nih.gov/31142508 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: https://pubmed.ncbi.nlm.nih.gov/31142508 Page: p.4910

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P00GULT	https://www.1pchem.com/search?query=1P00GULT
AK Scientific	2614AH	https://aksci.com/item_detail.php?cat=2614AH
AK Scientific	SYN5719	https://aksci.com/item_detail.php?cat=SYN5719
AKOS	AKOS028109171	http://akoscompounds.de/catalogue/AKosSamplesiSSretrieval.php?GUID=4e4caa52-3dca-4da0-b75a-caeae59e1096&IDNUMBERS=AKOS028109171
AOBIOUS INC	AOB87341	http://aobious.com/aobious/search?search_query=AOB87341
AstaTech	40576	http://astatechinc.com/CPSResult.php?CRNO=40576
BLD Pharm	BD631034	http://www.bldpharm.com/search/Search.html?keyword=BD631034
BOC Sciences	935888-69-0	http://www.bocsci.com/description.asp?cas=935888-69-0
Cayman Chemical	16269	http://www.caymanchem.com/app/template/Product.vm/catalog/16269
Chem Scene	CS-2767	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-2767
ChemShuttle	141848	https://www.chemshuttle.com/catalogsearch/result/?q=141848
KeyOrganics	AS-17020	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-17020
MedChem Express	HY-12113	https://www.medchemexpress.com/search.html?q=HY-12113&ft=&fa=&fp=
MolPort	MolPort-028-720-441	https://www.molport.com/shop/molecule-link/MolPort-028-720-441
MolPort	MolPort-035-395-758	https://www.molport.com/shop/molecule-link/MolPort-035-395-758
Molnova	M16697	https://www.molnova.com/en/serch-list.html?keywords=M16697
Selleck Chemicals	S7049	http://www.selleckchem.com/search.html?searchDTO.searchParam=S7049
ShangHai Biochempartner	BCP000868	http://www.biochempartner.com/search_BCP000868
ShangHai Biochempartner	BCP07603	http://www.biochempartner.com/search_BCP07603
TargetMol	T6041	https://www.targetmol.com/search?keyword=T6041
Toronto Research Chemicals	O669700	https://www.trc-canada.com/product-detail/?CatNum=O669700
eMolecules	46301158	https://orderbb.emolecules.com/search/#?query=46301158
eMolecules	49383347	https://orderbb.emolecules.com/search/#?query=49383347
mcule	MCULE-6520091555	https://mcule.com/MCULE-6520091555/
mcule	MCULE-8434983414	https://mcule.com/MCULE-8434983414/

PubMed

Title	Date	PubMed
Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047).	2009 May 14	19348473
A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma.	2010 Dec 2	20805366
Molecular mechanisms of acquired proteasome inhibitor resistance.	2012 Dec 13	22978849
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	22929803

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

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

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