WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H205730
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.
Hodoodo Cat#: H205730
Name: ONX-0914
CAS#: 960374-59-8
Chemical Formula: C31H40N4O7
Exact Mass: 580.29
Molecular Weight: 580.670
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
More Info: 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).
| 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 [12]. 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 | |
|---|---|---|---|
| Solubility | |||
| DMSO | 30.0 | 60.30 |
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. |
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