ONX-0914
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    WARNING: This product is for research use only, not for human or veterinary use.

MedKoo CAT#: 205730

CAS#: 960374-59-8

Description: ONX 0914 is an immunoproteasome inhibitor with potential treatment applications in autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease and lupus. ONX 0914 was designed to be a potent inhibitor of the immunoproteasome with minimal cross-reactivity for the constitutive proteasome. Recent evidence suggests that the immunoproteasome regulates the production of several inflammatory cytokines, including Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), IL-17, and IL-23. In preclinical models of rhematoid arthritis and lupus, ONX 0914 blocked progression of these diseases at well-tolerated doses. Preclinical studies are underway to evaluate the potential of ONX 0914 in the treatment of a range of autoimmune disorders.


Price and Availability

Size
Price

10mg
USD 150
100mg
USD 650
1g
USD 2950
Size
Price

25mg
USD 250
200mg
USD 950
2g
USD 4650
Size
Price

50mg
USD 450
500mg
USD 1750
5g
USD 8250

ONX-0914 purity > 98%, is in stock. The same day shipping out after order is received. Note: the estimated shipping out time for order > 3g may be 2 weeks.


Chemical Structure

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Theoretical Analysis

MedKoo Cat#: 205730
Name: ONX-0914
CAS#: 960374-59-8
Chemical Formula: C31H40N4O7
Exact Mass: 580.2897
Molecular Weight: 580.6719
Elemental Analysis: C, 64.12; H, 6.94; N, 9.65; O, 19.29


Synonym: ONX 0914; ONX0914; ONX-0914; PR957; PR-957; PR 957.

IUPAC/Chemical Name: (S)-3-(4-methoxyphenyl)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide

InChi Key: WQAVPPWWLLVGFK-VTNASVEKSA-N

InChi Code: InChI=1S/C31H40N4O7/c1-21(32-27(36)19-35-13-15-41-16-14-35)29(38)34-26(18-23-9-11-24(40-3)12-10-23)30(39)33-25(28(37)31(2)20-42-31)17-22-7-5-4-6-8-22/h4-12,21,25-26H,13-20H2,1-3H3,(H,32,36)(H,33,39)(H,34,38)/t21-,25-,26-,31+/m0/s1

SMILES Code: O=C(N[C@@H](CC1=CC=CC=C1)C([C@]2(C)OC2)=O)[C@@H](NC([C@@H](NC(CN3CCOCC3)=O)C)=O)CC4=CC=C(OC)C=C4


Technical Data

Appearance:
white to off-white solid powder

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

Safety Data Sheet (MSDS):

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).

Harmonized System Code:
293490


Additional Information

Onyx is developing ONX 0914 to be an inhibitor of the immunoproteasome, with minimal cross-reactivity for the constitutive proteasome. In preclinical models of rheumatoid arthritis and lupus, ONX 0914 blocked progression of these diseases at well tolerated doses. The Company is conducting preclinical studies to evaluate the potential clinical applications of ONX 0914 in the treatment of autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease and lupus.
  
According to wikipedia.com, ONX 0914's former name was PR-957, which was developed by Proteolix. Proteolix was acquired by Onyx Pharmaceuticals in 2009 for $810 million (nominal value). Onyx renamed PR-047 to "ONX 0912 ( Oprozomib) " and PR-957 to "ONX 0914". (source: http://en.wikipedia.org/wiki/Proteolix).
 
 


References

1: Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Stefanidis I. Proteasome or immunoproteasome inhibitors cause apoptosis in human renal tubular epithelial cells under normoxic and hypoxic conditions. Int Urol Nephrol. 2016 Feb 26. [Epub ahead of print] PubMed PMID: 26920131.

2: Mundt S, Basler M, Buerger S, Engler H, Groettrup M. Inhibiting the immunoproteasome exacerbates the pathogenesis of systemic Candida albicans infection in mice. Sci Rep. 2016 Jan 18;6:19434. doi: 10.1038/srep19434. PubMed PMID: 26776888; PubMed Central PMCID: PMC4726078.

3: Walker-Caulfield ME, Guo Y, Johnson RK, McCarthy CB, Fitz-Gibbon PD, Lucchinetti CF, Howe CL. NFκB signaling drives pro-granulocytic astroglial responses to neuromyelitis optica patient IgG. J Neuroinflammation. 2015 Sep 30;12:185. doi: 10.1186/s12974-015-0403-8. PubMed PMID: 26423139; PubMed Central PMCID: PMC4590277.

4: Howland SW, Ng GX, Chia SK, Rénia L. Investigating proteasome inhibitors as potential adjunct therapies for experimental cerebral malaria. Parasite Immunol. 2015 Nov;37(11):599-604. doi: 10.1111/pim.12277. PubMed PMID: 26366636.

5: Zhang HM, Fu J, Hamilton R, Diaz V, Zhang Y. The mammalian target of rapamycin modulates the immunoproteasome system in the heart. J Mol Cell Cardiol. 2015 Sep;86:158-67. doi: 10.1016/j.yjmcc.2015.07.027. Epub 2015 Aug 1. PubMed PMID: 26239133.

6: Zilberberg J, Matos J, Dziopa E, Dziopa L, Yang Z, Kirk CJ, Assefnia S, Korngold R. Inhibition of the Immunoproteasome Subunit LMP7 with ONX 0914 Ameliorates Graft-versus-Host Disease in an MHC-Matched Minor Histocompatibility Antigen-Disparate Murine Model. Biol Blood Marrow Transplant. 2015 Sep;21(9):1555-64. doi: 10.1016/j.bbmt.2015.06.010. Epub 2015 Jun 18. PubMed PMID: 26093043.

7: Harshbarger W, Miller C, Diedrich C, Sacchettini J. Crystal structure of the human 20S proteasome in complex with carfilzomib. Structure. 2015 Feb 3;23(2):418-24. doi: 10.1016/j.str.2014.11.017. Epub 2015 Jan 15. PubMed PMID: 25599644.

8: Huber EM, Heinemeyer W, Groll M. Bortezomib-resistant mutant proteasomes: structural and biochemical evaluation with carfilzomib and ONX 0914. Structure. 2015 Feb 3;23(2):407-17. doi: 10.1016/j.str.2014.11.019. Epub 2015 Jan 15. PubMed PMID: 25599643.

9: Arciniega M, Beck P, Lange OF, Groll M, Huber R. Differential global structural changes in the core particle of yeast and mouse proteasome induced by ligand binding. Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9479-84. doi: 10.1073/pnas.1408018111. Epub 2014 Jun 16. PubMed PMID: 24979800; PubMed Central PMCID: PMC4084421.

10: Niewerth D, Kaspers GJ, Assaraf YG, van Meerloo J, Kirk CJ, Anderl J, Blank JL, van de Ven PM, Zweegman S, Jansen G, Cloos J. Interferon-γ-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance in human hematological cell lines. J Hematol Oncol. 2014 Jan 13;7:7. doi: 10.1186/1756-8722-7-7. PubMed PMID: 24418325; PubMed Central PMCID: PMC3896789.

11: Basler M, Mundt S, Muchamuel T, Moll C, Jiang J, Groettrup M, Kirk CJ. Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis. EMBO Mol Med. 2014 Feb;6(2):226-38. doi: 10.1002/emmm.201303543. Epub 2014 Jan 16. PubMed PMID: 24399752; PubMed Central PMCID: PMC3927957.

12: Niewerth D, Franke NE, Jansen G, Assaraf YG, van Meerloo J, Kirk CJ, Degenhardt J, Anderl J, Schimmer AD, Zweegman S, de Haas V, Horton TM, Kaspers GJ, Cloos J. Higher ratio immune versus constitutive proteasome level as novel indicator of sensitivity of pediatric acute leukemia cells to proteasome inhibitors. Haematologica. 2013 Dec;98(12):1896-904. doi: 10.3324/haematol.2013.092411. Epub 2013 Sep 20. PubMed PMID: 24056819; PubMed Central PMCID: PMC3856965.

13: Mulder A, Heidt S, Vergunst M, Roelen DL, Claas FH. Proteasome inhibition profoundly affects activated human B cells. Transplantation. 2013 Jun 15;95(11):1331-7. doi: 10.1097/TP.0b013e3182911739. PubMed PMID: 23624544.

14: Stein ML, Groll M. Applied techniques for mining natural proteasome inhibitors. Biochim Biophys Acta. 2014 Jan;1843(1):26-38. doi: 10.1016/j.bbamcr.2013.01.017. Epub 2013 Jan 27. Review. PubMed PMID: 23360979.

15: Verbrugge SE, Al M, Assaraf YG, Niewerth D, van Meerloo J, Cloos J, van der Veer M, Scheffer GL, Peters GJ, Chan ET, Anderl JL, Kirk CJ, Zweegman S, Dijkmans BA, Lems WF, Scheper RJ, de Gruijl TD, Jansen G. Overcoming bortezomib resistance in human B cells by anti-CD20/rituximab-mediated complement-dependent cytotoxicity and epoxyketone-based irreversible proteasome inhibitors. Exp Hematol Oncol. 2013 Jan 10;2(1):2. doi: 10.1186/2162-3619-2-2. PubMed PMID: 23305345; PubMed Central PMCID: PMC3560160.

16: Kalim KW, Basler M, Kirk CJ, Groettrup M. Immunoproteasome subunit LMP7 deficiency and inhibition suppresses Th1 and Th17 but enhances regulatory T cell differentiation. J Immunol. 2012 Oct 15;189(8):4182-93. doi: 10.4049/jimmunol.1201183. Epub 2012 Sep 14. PubMed PMID: 22984077.

17: Nagayama Y, Nakahara M, Shimamura M, Horie I, Arima K, Abiru N. Prophylactic and therapeutic efficacies of a selective inhibitor of the immunoproteasome for Hashimoto's thyroiditis, but not for Graves' hyperthyroidism, in mice. Clin Exp Immunol. 2012 Jun;168(3):268-73. doi: 10.1111/j.1365-2249.2012.04578.x. PubMed PMID: 22519588; PubMed Central PMCID: PMC3390477.

18: Basler M, Groettrup M. Immunoproteasome-specific inhibitors and their application. Methods Mol Biol. 2012;832:391-401. doi: 10.1007/978-1-61779-474-2_27. PubMed PMID: 22350900.

19: Huber EM, Basler M, Schwab R, Heinemeyer W, Kirk CJ, Groettrup M, Groll M. Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity. Cell. 2012 Feb 17;148(4):727-38. doi: 10.1016/j.cell.2011.12.030. PubMed PMID: 22341445.

20: Verbrugge SE, Assaraf YG, Dijkmans BA, Scheffer GL, Al M, den Uyl D, Oerlemans R, Chan ET, Kirk CJ, Peters GJ, van der Heijden JW, de Gruijl TD, Scheper RJ, Jansen G. Inactivating PSMB5 mutations and P-glycoprotein (multidrug resistance-associated protein/ATP-binding cassette B1) mediate resistance to proteasome inhibitors: ex vivo efficacy of (immuno)proteasome inhibitors in mononuclear blood cells from patients with rheumatoid arthritis. J Pharmacol Exp Ther. 2012 Apr;341(1):174-82. doi: 10.1124/jpet.111.187542. Epub 2012 Jan 10. PubMed PMID: 22235146.