ONX-0914

• CAT Number: I005694
• CAS Number: 960374-59-8
• Molecular Formula: C₃₁H₄₀N₄O₇
• Molecular Weight: 580.67
• Purity: ≥95%
• Target: Proteasome
• Solubility: DMSO: ≥ 35 mg/mL
• Storage: -20°C
• IC50: ~10 nM
• InChI: 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
• InChIKey: WQAVPPWWLLVGFK-ZCKRSBOQSA-N
• SMILES: CC(C(=O)NC(CC1=CC=C(C=C1)OC)C(=O)NC(CC2=CC=CC=C2)C(=O)C3(CO3)C)NC(=O)CN4CCOCC4

ONX-0914 (CAT: I005694), also known as PR-957, is a potent and selective inhibitor of the immunoproteasome with minimal cross-reactivity for the constitutive proteasome. It exhibits 20- to 40-fold selectivity for LMP7 over other sensitive sites, such as β5 or LMP2. By blocking the presentation of LMP7-specific antigens, ONX-0914 inhibits the immune response mediated by MHC-I–restricted antigens both in vitro and in vivo. Additionally, ONX-0914 selectively inhibits the production of interleukin-23 (IL-23), interferon-gamma, IL-2, tumor necrosis factor-α (TNF-α), and IL-6 by monocytes and T cells. These properties make ONX-0914 a promising candidate for modulating immune responses and potentially treating immune-related disorders.

Reference

1. Eur J Microbiol Immunol (Bp). 2017 Sep 25;7(3):234-245. doi: 10.1556/1886.2017.00025. eCollection 2017 Sep.
Low Neurotoxicity of ONX-0914 Supports the Idea of Specific Immunoproteasome Inhibition as a Side-Effect-Limiting, Therapeutic Strategy.
von Brzezinski L(1), Säring P(1), Landgraf P(1), Cammann C(2), Seifert U(2), Dieterich DC(1)(3).
Author information:
(1)Neural Plasticity and Communication, Institute for Pharmacology and Toxicology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany. (2)Friedrich Loeffler Institute for Medical Microbiology, Greifswald, Germany. (3)Center for Behavioral Brain Sciences, Magdeburg, Germany.
Application of the proteasome inhibitor Bortezomib for the treatment of haematopoietic malignancies such as multiple myeloma significantly improves the average overall survival of patients. However, one of the most severe side effects is the development of peripheral neuropathies caused by neurotoxic effects of Bortezomib limiting its therapeutic efficacy. With ONX-0914 a specific inhibitor of the β5i (LMP7)-immunosubunit containing proteasomes was developed that targets exclusively the proteasome subtypes mainly expressed in immune cells including B lymphocytes as the origin of multiple myeloma. Furthermore, immunosubunitspecific inhibitors have been shown to be promising tools for the therapy of autoimmune disorders. In the presented study, we analysed the concentration-dependent impact of both inhibitors on primary neurons regarding survival rate, morphological changes, and overall viability. Our results clearly demonstrate that ONX-0914, compared to Bortezomib, is less neurotoxic suggesting its potential as a putative antineoplastic drug and as a candidate for the treatment of autoimmune disorders affecting the peripheral and/or central nervous system.
2. Structure. 2015 Feb 3;23(2):407-17. doi: 10.1016/j.str.2014.11.019. Epub 2015 Jan 15.
Bortezomib-resistant mutant proteasomes: structural and biochemical evaluation with carfilzomib and ONX 0914.
Huber EM(1), Heinemeyer W(2), Groll M(3).
Author information:
(1)Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstraße 4, 85747 Garching, Germany. Electronic address: . (2)Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstraße 4, 85747 Garching, Germany. (3)Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstraße 4, 85747 Garching, Germany. Electronic address: .
Inhibition of the 20S proteasome by bortezomib (Velcade) constitutes a successfully applied therapy for blood cancer. However, emerging resistance restricts its medicinal use. For example, mutations in the proteolytically active β5-subunit of the proteasome, the main target of inhibitors, were reported to impair drug binding and thus to reduce therapeutic efficacy. Using yeast as a model system, we describe here a systematic evaluation of these mutations by cell growth analysis, proteasome inhibition assays, and X-ray crystallography. The 11 mutants examined display decreased proliferation rates, impaired proteolytic activity, and marked resistance to bortezomib as well as the α/',β/'-epoxyketone inhibitors carfilzomib (Kyprolis) and ONX 0914, while the second-generation compound carfilzomib was the least affected. In total, 49 proteasome X-ray structures, including structural data on proteasome-carfilzomib complexes, reveal three distinct molecular mechanisms that hamper both drug binding and natural substrate turnover to an extent that is still compatible with cell survival.