Molecular Weight(MW): 580.67
ONX-0914 (PR-957) is a potent and selective immunoproteasome inhibitor with minimal cross-reactivity for the constitutive proteasome in a cell-free assay.
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|Description||ONX-0914 (PR-957) is a potent and selective immunoproteasome inhibitor with minimal cross-reactivity for the constitutive proteasome in a cell-free assay.|
|Features||The first highly selective, small molecule inhibitor of the immunoproteasome. Potential use in cancer and autoimmune diseases (e.g. rheumatoid arthritis, inflammatory bowel disease, and lupus).|
ONX-0914 is 20- to 40-fold more selective for LMP7 over the next most sensitive sites, β5 or LMP2. ONX-0914 blocks presentation of LMP7-specific, MHC-I–restricted antigens in vitro and in vivo with minimal cross-reactivity for the constitutive proteasome. Selective inhibition of LMP7 by ONX-0914 blocks production of interleukin-23 (IL-23) by activated monocytes and interferon-gamma and IL-2 by T cells. LMP7 inhibition blocks production of IL-23 by ~90% and of tumor necrosis factor-α (TNF-α) and IL-6 by ~50%.
|In vivo||In mouse models of rheumatoid arthritis and lupus, ONX-0914 treatment reverses signs of disease and results in reductions in cellular infiltration, cytokine production and autoantibody levels at well-tolerated doses. The maximum tolerated dose (MTD) of ONX-0914 in mice to be 30 mg/kg body weight. IFN-g release is inhibited by ~60% at LMP7-selective concentrations of ONX-0914 and by ~90% at higher concentrations. Production of IL-2 is also inhibited by ~50%.|
|In vitro||DMSO||100 mg/mL (172.21 mM)|
|Ethanol||100 mg/mL (172.21 mM)|
|In vivo||2% DMSO+castor oil||10 mg/mL|
* 1 mg/ml means slightly soluble or insoluble.
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