Oprozomib (ONX 0912)
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MedKoo CAT#: 205565

CAS#: 935888-69-0

Description: Oprozomibm, also known as ONX 0912 and PR 047 , is a n orally bioavailable proteasome inhibitor with potential antineoplastic activity. ONX 0912 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. Proteasomes are large protease complexes that degrade unneeded or damaged proteins that have been ubiquitinated.


Chemical Structure

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Oprozomib (ONX 0912)
CAS# 935888-69-0

Theoretical Analysis

MedKoo Cat#: 205565
Name: Oprozomib (ONX 0912)
CAS#: 935888-69-0
Chemical Formula: C25H32N4O7S
Exact Mass: 532.19917
Molecular Weight: 532.61
Elemental Analysis: C, 56.38; H, 6.06; N, 10.52; O, 21.03; S, 6.02

Price and Availability

Size Price Availability Quantity
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 750.0 Ready to ship
200.0mg USD 1250.0 Ready to ship
500.0mg USD 1950.0 Ready to ship
1.0g USD 2750.0 2 Weeks
2.0g USD 3950.0 2 Weeks
5.0g USD 5950.0 2 Weeks
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Synonym: ONX0912; ONX-0912; ONX 0912; PR047; PR-047; PR 047.

IUPAC/Chemical Name: N-((S)-3-methoxy-1-(((S)-3-methoxy-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide

InChi Key: SWZXEVABPLUDIO-WSZYKNRRSA-N

InChi Code: 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

SMILES Code: O=C(C1=CN=C(C)S1)N[C@@H](COC)C(N[C@@H](COC)C(N[C@@H](CC2=CC=CC=C2)C([C@]3(C)OC3)=O)=O)=O

Appearance: white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Oprozomib (ONX 0912; PR047) is an inhibitor for CT-L activity of 20S proteasome β5/LMP7 with IC50 of 36 nM/82 nM and a 20S proteasome target.
In vitro activity: This study aimed to evaluate the anti-tumor effect of a new generation of protease inhibitor, oprozomib (OPZ), used alone and in combination with cisplatin, also called CDDP, on cervical cancer. Five different types of cervical cancer cell lines - HeLa, Caski, HeLa-CDDP, C33a, and SiHa - and one nontransformed cervical cell line - HaCaT -were treated with OPZ alone or in combination with cisplatin. The inhibitory effects of OPZ and cisplatin on the proliferation of cervical cancer cells were then analyzed using cytotoxicity tests, flow cytometry, and Western blotting. It was found that OPZ alone or in combination with cisplatin can reduce the proliferation of the five types of cancer cells by enhancing the lysis of caspase-3 and PARP and inducing cancer cell apoptosis. In the combined treatment, OPZ was found to inhibit the degradation of inhibitory factor κB alpha induced by cisplatin, thereby inhibiting the activation of NF-κB, which causes cisplatin resistance, and enhancing the sensitivity of the tumor cells to cisplatin. Moreover, OPZ promoted the phosphorylation of the apoptosis signaling pathway JNK that was activated by cisplatin, thereby inducing tumor cell apoptosis. These findings provide a theoretical basis for the clinical use of OPZ alone and in combination with cisplatin in the treatment of cervical cancer. J Biol Regul Homeost Agents. Mar-Apr 2021;35(2):559-569
In vivo activity: A marked growth inhibitory effect of ONX 0912 was observed in 2 distinct human MM xenograft mouse models. INA-6 MM cells are injected directly into human bone chips that are implanted subcutaneously in SCID mice, and MM cell growth is assessed by serial measurements of circulating levels of soluble human IL-6R in mouse serum. A more robust growth inhibition of tumor occurred in mice receiving oral doses (30 mg/kg or 50 mg/kg) of ONX 0912 than in mice injected with vehicle alone (Figure 5B). Importantly, treatment of tumor-bearing mice with ONX 0912, but not vehicle alone, significantly prolonged survival (P = .03; Figure 5C). A head-to-head analysis of carfilzomib and ONX 0912 showed equipotent antitumor activity in a human plasmacytoma xenograft mouse model. The findings are consistent with reported antitumor activity of ONX 0912 in nonHodgkin lymphoma (NHL) tumor xenograft and mouse syngeneic models. ONX 0912 is well tolerated, inhibits tumor growth, and prolongs survival in mice Blood. 2010 Dec 2; 116(23): 4906–4915.

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 5.0 9.4

Preparing Stock Solutions

The following data is based on the product molecular weight 532.61 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Li QZ, Sun LP, Shi HY, Chen Y, Shen H. The new-generation proteasome inhibitor oprozomib increases the sensitivity of cervical cancer cells to cisplatin-induced apoptosis. J Biol Regul Homeost Agents. 2021 Mar-Apr;35(2):559-569. doi: 10.23812/20-504-A. PMID: 33973461. 2. Fan Y, Liang Z, Zhang J, You G. Oral Proteasomal Inhibitors Ixazomib, Oprozomib, and Delanzomib Upregulate the Function of Organic Anion Transporter 3 (OAT3): Implications in OAT3-Mediated Drug-Drug Interactions. Pharmaceutics. 2021 Feb 28;13(3):314. doi: 10.3390/pharmaceutics13030314. PMID: 33670955; PMCID: PMC7997269. 3. Chauhan D, Singh AV, Aujay M, Kirk CJ, Bandi M, Ciccarelli B, Raje N, Richardson P, Anderson KC. A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood. 2010 Dec 2;116(23):4906-15. doi: 10.1182/blood-2010-04-276626. Epub 2010 Aug 30. PMID: 20805366; PMCID: PMC3321748. 4. Semren N, Habel-Ungewitter NC, Fernandez IE, Königshoff M, Eickelberg O, Stöger T, Meiners S. Validation of the 2nd Generation Proteasome Inhibitor Oprozomib for Local Therapy of Pulmonary Fibrosis. PLoS One. 2015 Sep 4;10(9):e0136188. doi: 10.1371/journal.pone.0136188. PMID: 26340365; PMCID: PMC4560391.
In vitro protocol: 1. Li QZ, Sun LP, Shi HY, Chen Y, Shen H. The new-generation proteasome inhibitor oprozomib increases the sensitivity of cervical cancer cells to cisplatin-induced apoptosis. J Biol Regul Homeost Agents. 2021 Mar-Apr;35(2):559-569. doi: 10.23812/20-504-A. PMID: 33973461. 2. Fan Y, Liang Z, Zhang J, You G. Oral Proteasomal Inhibitors Ixazomib, Oprozomib, and Delanzomib Upregulate the Function of Organic Anion Transporter 3 (OAT3): Implications in OAT3-Mediated Drug-Drug Interactions. Pharmaceutics. 2021 Feb 28;13(3):314. doi: 10.3390/pharmaceutics13030314. PMID: 33670955; PMCID: PMC7997269.
In vivo protocol: 1. Chauhan D, Singh AV, Aujay M, Kirk CJ, Bandi M, Ciccarelli B, Raje N, Richardson P, Anderson KC. A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood. 2010 Dec 2;116(23):4906-15. doi: 10.1182/blood-2010-04-276626. Epub 2010 Aug 30. PMID: 20805366; PMCID: PMC3321748. 2. Semren N, Habel-Ungewitter NC, Fernandez IE, Königshoff M, Eickelberg O, Stöger T, Meiners S. Validation of the 2nd Generation Proteasome Inhibitor Oprozomib for Local Therapy of Pulmonary Fibrosis. PLoS One. 2015 Sep 4;10(9):e0136188. doi: 10.1371/journal.pone.0136188. PMID: 26340365; PMCID: PMC4560391.

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1. Use of peptide epoxyketone proteasome inhibitors for metastasis suppression By Kirk, Christopher J.; Jiang, Jing From PCT Int. Appl. (2011), WO 2011060179 A1 20110519.

2. Combination of proteasome inhibitors and anti-hepatitis medication for treating hepatitis By Schubert, Ulrich From PCT Int. Appl. (2011), WO 2011009961 A1 20110127.

3. A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma By Chauhan, Dharminder; Singh, Ajita V.; Aujay, Monette; Kirk, Christopher J.; Bandi, Madhavi; Ciccarelli, Bryan; Raje, Noopur; Richardson, Paul; Anderson, Kenneth C. From Blood (2010), 116(23), 4906-4915.

4. Preparation and thermal properties of crystalline tripeptide epoxy ketone protease inhibitors By Phiasivongsa, Pasit; Sehl, Louis C. From PCT Int. Appl. (2010), WO 2010108172 A1 20100923.

5. Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in Waldenstrom macroglobulinemia By Roccaro, Aldo M.; Sacco, Antonio; Aujay, Monette; Ngo, Hai T.; Azab, Abdel Kareem; Azab, Feda; Quang, Phong; Maiso, Patricia; Runnels, Judith; Anderson, Kenneth C.; et al From Blood (2010), 115(20), 4051-4060.

6. Use of quinazoline derivatives for the treatment of hematologic malignancies, inflammatory and autoimmune disorders By Gallatin, Michael W.; Ulrich, Roger G.; Giese, Neill From PCT Int. Appl. (2010), WO 2010057048 A1 20100520.

7. Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy By Dick, Lawrence R.; Fleming, Paul E. From Drug Discovery Today (2010), 15(5/6), 243-249.

8. Design and Synthesis of an Orally Bioavailable and Selective Peptide Epoxyketone Proteasome Inhibitor (PR-047) By Zhou, Han-Jie; Aujay, Monette A.; Bennett, Mark K.; Dajee, Maya; Demo, Susan D.; Fang, Ying; Ho, Mark N.; Jiang, Jing; Kirk, Christopher J.; Laidig, Guy J.; et al From Journal of Medicinal Chemistry (2009), 52(9), 3028-3038.

9. Preparation of peptide epoxides and peptide aziridines as enzyme inhibitors, especially N-terminal nucleophile hydrolase inhibitors, for treating diseases By Zhou, Han-Jie; Laidig, Guy J.; Shenk, Kevin D.; Sun, Congcong M. From PCT Int. Appl. (2008), WO 2008140782 A2 20081120.

10. Compounds for enzyme inhibition By Zhou, Han-Jie; Sun, Congcong M.; Shenk, Kevin D.; Laidig, Guy J. From U.S. Pat. Appl. Publ. (2007), US 20070105786 A1 20070510.



Additional Information

ONX 0912 is a tripeptide epoxyketone, which inhibits growth and induces apoptosis in MM cells resistant to conventional and bortezomib therapies. The anti-MM activity of ONX-0912 is associated with activation of caspase-8, caspase-9, caspase-3, and poly(ADP) ribose polymerase, as well as inhibition of migration of MM cells and angiogenesis. ONX 0912 , like bortezomib, predominantly inhibits chymotrypsin-like activity of the proteasome and is distinct from bortezomib in its chemical structure. Importantly, ONX 0912 is orally bioactive. In animal tumor model studies, ONX 0912 significantly reduced tumor progression and prolonged survival. Immununostaining of MM tumors from ONX 0912 -treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Finally, ONX 0912 enhances anti-MM activity of bortezomib, lenalidomide dexamethasone, or pan-histone deacetylase inhibitor. Taken together, our study provides the rationale for clinical protocols evaluating ONX 0912 , either alone or in combination, to improve patient outcome in MM. (source: Blood. 2010 Dec 2;116(23):4906-15.)
 
Onyx is developing ONX 0912, a novel oral proteasome inhibitor. ONX 0912 inhibits the 20S proteasome that primarily targets chymotrypsin-like activity. ONX 0912 is distinct from carfilzomib, although the compound is based on the same chemistry that is employed to selectively target the proteasome. As an orally-dosed agent, ONX 0912 is designed to provide prolonged proteasome inhibition and combinability with other available therapies with the convenience of an oral therapy. (source: http://www.onyx-pharm.com/clinical-development/onx-091).