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

Technical Data

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).
  
  
 

References

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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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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.

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