The immunoproteasome is a class of proteasome predominantly synthesized in monocytes and lymphocytes. ONX-0914 is a selective inhibitor of low-molecular mass polypeptide-7 (LMP7), the chymotrypsin-like subunit of the immunoproteasome. In human peripheral blood mononuclear cells (PBMCs), 100 nM ONX-0914 blocked the activity of LMP7 by 480% with minimal inhibitory effect on LMP2 or MECL-1. ONX-0914 at 200 nM also inhibited the production of
inflammatory cytokines, such as IL-23, TNF-α and IL-6, in LPS-stimulated human PBMCs. ONX-0914 at the doses of 25-300 nM inhibited chymotrypsin-like activity of liver proteasomes isolated from WT mice but not Psmb8-/- mice. In BALB/c mice, an intravenous administration of ONX-0914 at 1-10 mg/kg inhibited the activity of LMP7 in both blood and kidney. The intravenous treatment of female C57BL/6 mice with ONX-0914 (6 mg/kg) for 5 days suppressed the infection induced by recombinant vaccinia virus expressing UTY protein. In a mouse model of collagen antibody-induced arthritis, ONX-0914 at 2, 6, or 10 mg/kg delayed disease progression in a concentration-dependent manner and completely ameliorated visible clinical signs at the dose of 10 mg/kg[2].
作用机制
ONX-0914 is a selective inhibitor for the chymotrypsin-like subunit of immunoproteasome, LMP7. It contains a ketoepoxide pharmacophore that covalently modifies the proteasomal active sites of LMP7.
ONX-0914 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
human Raji cells
Function assay
Inhibition of proteasome subunit beta-5i in human Raji cells using BODIPY-NC005 by fluorescent densitometry, IC50=5.7 nM
25006746
human Raji cells
Function assay
Inhibition of 20s proteasome subunit beta-5c in human Raji cells using BODIPY-NC005 by fluorescent densitometry, IC50=0.054 μM
25006746
human Raji cells
Function assay
Inhibition of proteasome subunit beta-1i in human Raji cells using BODIPY- epoxomicin by fluorescent densitometry, IC50=0.46 μM
25006746
human Raji cells
Function assay
Inhibition of proteasome subunit beta-2i in human Raji cells using BODIPY- epoxomicin by fluorescent densitometry, IC50=0.59 μM
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