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MedKoo CAT#: 205565
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.
MedKoo Cat#: 205565
Name: Oprozomib (ONX 0912)
Chemical Formula: C25H32N4O7S
Exact Mass: 532.19917
Molecular Weight: 532.60918
Elemental Analysis: C, 56.38; H, 6.06; N, 10.52; O, 21.03; S, 6.02
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
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).
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.
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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.
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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.