OPROZOMIB

Investigational

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

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

Molecular Formula	C25H32N4O7S
Molecular Weight	532.609
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	4 / 4
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

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	Inhibitor 8,297		82.0 nM [IC50]
Proteasome subunit beta type-5 6	Inhibitor 8,297		36.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Multiple myeloma 159	Primary	Phase II 1,132	Unknown
Waldenström's macroglobulinemia 7	Primary	Phase II 1,132	Unknown
Hepatocellular carcinoma 83	Primary	Phase II 1,132	Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
760 ng/mL	150 mg 1 times / day multiple, oral		OPROZOMIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
1070 ng × h/mL	150 mg 1 times / day multiple, oral		OPROZOMIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
0.843 h	150 mg 1 times / day multiple, oral		OPROZOMIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
330 mg 2 times / week multiple, oral Highest studied dose	unhealthy, ADULT	DLT: Diarrhea, Hypotension...
150 mg 1 times / day multiple, oral MTD	unhealthy, ADULT
240 mg 1 times / day multiple, oral MTD	unhealthy, ADULT	DLT: Tumor lysis syndrome...
300 mg 2 times / week multiple, oral MTD	unhealthy, ADULT	DLT: Hypotension...
90 mg 2 times / day multiple, oral MTD	unhealthy, ADULT	DLT: Hypophosphatemia...

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AEs

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AE	Significance	Dose	Population
Diarrhea	14.3% DLT	330 mg 2 times / week multiple, oral Highest studied dose	unhealthy, ADULT
Hypotension	14.3% DLT	330 mg 2 times / week multiple, oral Highest studied dose	unhealthy, ADULT
Tumor lysis syndrome	25% DLT	240 mg 1 times / day multiple, oral MTD	unhealthy, ADULT
Hypotension	14.3% DLT	300 mg 2 times / week multiple, oral MTD	unhealthy, ADULT
Hypophosphatemia	grade 3, 14.3% DLT	90 mg 2 times / day multiple, oral MTD	unhealthy, ADULT

Showing 1 to 5 of 11 entries

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Sourcing

Sourcing

Show entries

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

Showing 1 to 5 of 25 entries

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PubMed

Show entries

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

Showing 1 to 4 of 4 entries

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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).