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 细胞实验
Cell Line
Concentration
Treated Time
Description
References
CLU177 cells
10 nM
24 hours
To study the effect of ONX-0914 on PA-induced insulin-glucose axis imbalance, results showed that ONX-0914 restored the decrease in AKT phosphorylation caused by PA.
J Neuroinflammation. 2024 Aug 2;21(1):191.
PC3 cells
300 nM
24 hours
To investigate the effect of ONX-0914 on apoptosis of CRPC cells, results showed that ONX-0914 induces CRPC cell apoptosis via activation of the unfolded protein response (UPR).
Br J Cancer. 2023 Mar;128(7):1377-1390.
22Rv.1 cells
300 nM
24 hours
To investigate the effect of ONX-0914 on apoptosis of CRPC cells, results showed that ONX-0914 induces CRPC cell apoptosis via activation of the unfolded protein response (UPR).
Br J Cancer. 2023 Mar;128(7):1377-1390.
TRAMP-C2 cells
300 nM
24 hours
ONX 0914 induced poly-ubiquitin accumulation in TRAMP-C2 cells and triggered apoptosis via both intrinsic and extrinsic pathways.
Oncoimmunology. 2022 Dec 15;12(1):2156091.
DU145 cells
300 nM
24 hours
ONX 0914 induced poly-ubiquitin accumulation in DU145 cells and triggered apoptosis via both intrinsic and extrinsic pathways.
Oncoimmunology. 2022 Dec 15;12(1):2156091.
Human peripheral blood mononuclear cells (PBMCs)
100 nM
24 hours
ONX-0914 reduced the secretion of GM-CSF and IL-23
EMBO Mol Med. 2014 Feb;6(2):226-38.
Mouse splenic CD4+ T cells
300 nM
3 days
ONX-0914 inhibited Th17 cell differentiation
EMBO Rep. 2018 Dec;19(12):e46512.
Alveolar Macrophages (AMs)
0.2 µM
6 hours
To evaluate the inhibitory effect of ONX-0914 on M1 macrophage polarization, results showed that ONX-0914 significantly suppressed the expression of M1 marker genes.
Adv Sci (Weinh). 2024 Nov;11(44):e2405318.
RAW264.7 cells
0.2 µM
6 hours
To evaluate the inhibitory effect of ONX-0914 on CSE-induced M1 polarization, results showed that ONX-0914 significantly suppressed the expression of M1 marker genes.
Adv Sci (Weinh). 2024 Nov;11(44):e2405318.
Mouse splenocytes
300 nM
Overnight
ONX-0914 reduced the surface expression of H-2Kb
EMBO Rep. 2018 Dec;19(12):e46512.
Human PBMCs
300 nM
Overnight
ONX-0914 inhibited IL-6 secretion
EMBO Rep. 2018 Dec;19(12):e46512.
ONX-0914 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
DSS-induced colitis
Subcutaneous injection
10 mg/kg
Daily for 5 days
ONX-0914 protected mice from colitis
EMBO Rep. 2018 Dec;19(12):e46512.
Mice
CRPC tumor graft model
Subcutaneous injection
10 mg/kg
Every other day for 8 weeks
To investigate the inhibitory effect of ONX-0914 on CRPC tumor progression, results showed that ONX-0914 prevents CRPC progression by suppressing Th17-type inflammatory response and inducing CRPC cell apoptosis.
Br J Cancer. 2023 Mar;128(7):1377-1390.
Mice
TRAMP mouse model
Subcutaneous injection
10 mg/kg
Three times a week for 22 weeks
ONX 0914 treatment significantly inhibited prostate cancer growth in TRAMP mice, reduced the frequency of malignant prostatic lesions, and inhibited metastasis formation.
Oncoimmunology. 2022 Dec 15;12(1):2156091.
Mice
Experimental autoimmune encephalomyelitis (EAE)
Subcutaneous injection
10 mg/kg
Three times per week for 26 days
ONX-0914 significantly delayed the onset of EAE and reduced disease severity
EMBO Mol Med. 2014 Feb;6(2):226-38.
A/J mice
Coxsackievirus B3 (CVB3)-induced myocarditis model
Subcutaneous injection
10 mg/kg
Once daily for 5 days (from day 3 to day 7 post-infection)
To investigate the impact of ONX-0914 on myocarditis following CVB3 infection. Results showed that ONX-0914 treatment did not improve cardiac function, and inflammatory responses in heart tissue were unaffected.
Basic Res Cardiol. 2021 Feb 1;116(1):7
Mice
LDLr–/– and APOE*3-Leiden.CETP mice
Intraperitoneal injection
10 mg/kg
3 times per week for 7 weeks
ONX-0914 significantly reduced atherosclerosis, decreased dendritic cell and macrophage levels and their activation, reduced white adipose tissue mass, and improved markers of metabolic syndrome.
To evaluate the therapeutic effect of ONX-0914 on emphysema, results showed that ONX-0914 significantly improved lung function and alleviated lung inflammation.
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