ONX-0914

Biological Activity

Onx-0914 (PR-957) is a selective inhibitor of low molecular weight polypeptide 7 (LMP7), a chymotrypsin subunit of the immune proteasome. Onx-0914 blocks cytokine production and reduces the progression of experimental arthritis. Onx-0914 is a non-competitive irreversible inhibitor of mycobacterium proteasome (Ki=5.2 μM). Onx-0914 activates latent HIV-1 through HF-1-mediated p-TEFb activation.

Product Citations

• 

  2015 Mar.

  Effects of the Ubiquitin Proteasome Inhibitor on Ion Channels in Left Ventricular Hypertrophy and Association of rs3807989 with Atrial Fibrillation
  ONX-0914 purchased from AbMole

• 

  Sci Rep. 2020 Feb 25;10(1):3386.

  Gender-specific Changes in Energy Metabolism and Protein Degradation as Major Pathways Affected in Livers of Mice Treated With Ibuprofen
  ONX-0914 purchased from AbMole

• 

  Mol Cell Proteomics. 2016 Mar 28.

  Delineation of molecular pathways involved in cardiomyopathies caused by troponin T mutations.
  ONX-0914 purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Mol Cell Protomics (2016). Figure 4.ONX-0914 (Cat. No. M2071, Abmole Bioscience)
	Method	Immunoproteasome Activity Assays
	Cell Lines
	Concentrations	20μM
	Incubation Time	60 min
	Results	Levels of ubiquitinated proteins in total homogenates and oxidized proteins in cytosolic homogenates (as determined using the OxyBlot procedure, which detects carbonylated proteins) were increased in I79N mice relative to WT and R278C mice, consistent with impaired UPS function.

Protocol (for reference only)

Cell Experiment
Cell lines	ALL and AML cells
Preparation method	MTT cytotoxicity assay Cytotoxicity of bortezomib, dexamethasone, as well as their combination, and carfilzomib, ONX 0912, ONX 0914, and 5AHQ was determined using the MTT colorimetric dye reduction assay. For the drug combination study, CalcuSyn (Version 1.1.1 1996, Biosoft, Cambridge, UK) software was used to calculate a combination index (CI) based on the median-effect principle, for each drug combination tested.
Concentrations	0~1µM
Incubation time	96h

Animal Experiment
Animal models	RIP-GP mice model
Formulation	an aqueous solution of 10% (wt/vol) sulfobutylether-b-cyclodextrin and 10 mM sodium citrate (pH 3.5)
Dosages	6 mg per kg body weight for 10 d
Administration	a single i.v. bolus

Chemical Information

Molecular Weight	580.67
Formula	C31H40N4O7
CAS Number	960374-59-8
Solubility (25°C)	DMSO 40 mg/mL
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Basler M, et al. J Immunol. The antiviral immune response in mice devoid of immunoproteasome activity.

[2] Ichikawa HT, et al. Arthritis Rheum. Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells.