WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205730
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.
MedKoo Cat#: 205730
Chemical Formula: C31H40N4O7
Exact Mass: 580.2897
Molecular Weight: 580.67
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
Appearance: white to off-white solid powder
Purity: >97% (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:||ONX-0914 (PR-957) is a potent and selective inhibitor of immunoproteasome subunit LMP7 with an IC50 value of 10 nM (LMP7)|
|In vitro activity:||Since its original description as an LMP7-selective inhibitor, the molecular mechanism by which ONX 0914 affects the progression of auto-immune pathologies has remained elusive. Here, this study characterized the effect of ONX 0914-treatment on activation of primary human and murine T and B cells. IP inhibition by ONX 0914 reduces cytokine secretion and impairs T cell function. To understand these effects at the molecular level, IP inhibition in T cell activation was investigated within the first hours. CD4+ T cells from WT, LMP7-deficient or LMP2-deficient mice was purified and pulse-treated them for 2 h with ONX 0914 or DMSO before activation. Within 5 h of activation, ONX 0914-treated cells showed ~50% reduced CD69 up-regulation and IL-2 secretion in WT, but not in LMP7-deficient cells and only to a small extent in LMP2-deficient cells (Figures 1A,B). CD69 and IL-2 expression also showed a trend toward reduction at the mRNA level in ONX 0914-treated WT cells. These results suggested that IP inhibition, but not deficiency, impaired activation via an early cell-intrinsic mechanism, possibly involving impaired TCR-induced signaling. Front Immunol. 2018; 9: 2386.Published online 2018 Oct 26. doi: 10.3389/fimmu.2018.02386 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212513/|
|In vivo activity:||Viral infection of the heart is a known trigger of cardiac autoimmunity, with the ip enhancing systemic inflammatory responses after infection with a cardiotropic coxsackievirusB3 (CV). Here, ip-deficient A/J-LMP7−/− mice were used to investigate the role of ip-mediated effects on adaptive immunity in CV-triggered myocarditis. Aiming to define the impact of the systemic inflammatory storm under the control of ip proteolysis during CV infection, the ip in A/J mice were targeted with the inhibitor ONX 0914 after the first cycle of infection, when systemic inflammation has set in, well before cardiac inflammation. A comparison of ip-deficient A/J-LMP7−/− mice with their wild-type controls revealed the pro-inflammatory role of the ip for the onset and manifestation of cardiac autoimmunity, with both processes being reversible in wild-type mice by treatment with ONX 0914 . LMP7−/− mice resemble WT mice after ONX 0914 treatment with regard to the relative expression levels of the different ip subunits. They not only show a complete lack of LMP7, but also a profound reduction of Mecl-1 and lower LMP2 expression levels [40, 42]. Together with elevated PD-1 levels, an inhibitory immune checkpoint molecule, these data indicate that ONX 0914 steers the adaptive CD4+ T cell response towards an immune suppressive activity, which leads to less effective control of the virus in heart tissue upon treatment with ONX-0914. Basic Res Cardiol. 2021; 116(1): 7.Published online 2021 Feb 1. doi: 10.1007/s00395-021-00848-w https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851025/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 580.67 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.
|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. Schmidt C, Berger T, Groettrup M, Basler M. Immunoproteasome Inhibition Impairs T and B Cell Activation by Restraining ERK Signaling and Proteostasis. Front Immunol. 2018 Oct 26;9:2386. doi: 10.3389/fimmu.2018.02386. PMID: 30416500; PMCID: PMC6212513. 2.Downey-Kopyscinski S, Daily EW, Gautier M, Bhatt A, Florea BI, Mitsiades CS, Richardson PG, Driessen C, Overkleeft HS, Kisselev AF. An inhibitor of proteasome β2 sites sensitizes myeloma cells to immunoproteasome inhibitors. Blood Adv. 2018 Oct 9;2(19):2443-2451. doi: 10.1182/bloodadvances.2018016360. PMID: 30266819; PMCID: PMC6177641. 3. 1. Goetzke CC, Althof N, Neumaier HL, Heuser A, Kaya Z, Kespohl M, Klingel K, Beling A. Mitigated viral myocarditis in A/J mice by the immunoproteasome inhibitor ONX 0914 depends on inhibition of systemic inflammatory responses in CoxsackievirusB3 infection. Basic Res Cardiol. 2021 Feb 1;116(1):7. doi: 10.1007/s00395-021-00848-w. PMID: 33523326; PMCID: PMC7851025. 4. Kwak D, Wei G, Thompson LV, Kim JH. Short-Term ONX-0914 Administration: Performance and Muscle Phenotype in Mdx Mice. Int J Environ Res Public Health. 2020 Jul 19;17(14):5211. doi: 10.3390/ijerph17145211. PMID: 32707682; PMCID: PMC7399807.|
|In vitro protocol:||1. Schmidt C, Berger T, Groettrup M, Basler M. Immunoproteasome Inhibition Impairs T and B Cell Activation by Restraining ERK Signaling and Proteostasis. Front Immunol. 2018 Oct 26;9:2386. doi: 10.3389/fimmu.2018.02386. PMID: 30416500; PMCID: PMC6212513. 2.Downey-Kopyscinski S, Daily EW, Gautier M, Bhatt A, Florea BI, Mitsiades CS, Richardson PG, Driessen C, Overkleeft HS, Kisselev AF. An inhibitor of proteasome β2 sites sensitizes myeloma cells to immunoproteasome inhibitors. Blood Adv. 2018 Oct 9;2(19):2443-2451. doi: 10.1182/bloodadvances.2018016360. PMID: 30266819; PMCID: PMC6177641.|
|In vivo protocol:||1. Goetzke CC, Althof N, Neumaier HL, Heuser A, Kaya Z, Kespohl M, Klingel K, Beling A. Mitigated viral myocarditis in A/J mice by the immunoproteasome inhibitor ONX 0914 depends on inhibition of systemic inflammatory responses in CoxsackievirusB3 infection. Basic Res Cardiol. 2021 Feb 1;116(1):7. doi: 10.1007/s00395-021-00848-w. PMID: 33523326; PMCID: PMC7851025. 2. Kwak D, Wei G, Thompson LV, Kim JH. Short-Term ONX-0914 Administration: Performance and Muscle Phenotype in Mdx Mice. Int J Environ Res Public Health. 2020 Jul 19;17(14):5211. doi: 10.3390/ijerph17145211. PMID: 32707682; PMCID: PMC7399807.|
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.
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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.
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).