ONX-0914

ONX-0914 is a **selective, irreversible inhibitor of the immunoproteasome subunit LMP7 (also known as β5i)**. This small molecule **blocks the chymotrypsin-like activity of LMP7**, a component of the immunoproteasome that is upregulated in immune cells during inflammation. By inhibiting LMP7, ONX-0914 reduces the production of pro-inflammatory cytokines (such as IL-6, IFN-γ, TNF-α, and IL-23) and affects antigen presentation via MHC-I, thereby modulating both innate and adaptive immune responses[7][6][5]. \n\n**ONX-0914 has shown significant activity in preclinical models of autoimmune and immune-mediated diseases**, including multiple sclerosis, lupus, myasthenia gravis, myocarditis, inflammatory bowel disease, inflammatory arthritis, and psoriasis[6][2][5]. It has proven less neurotoxic than general proteasome inhibitors like bortezomib and exhibits cytotoxic effects primarily in cells expressing high levels of immunoproteasomes, such as certain cancer cells[3][4]. The compound was initially developed by Proteolix (later acquired by Onyx Pharmaceuticals, now part of Amgen)[7].