ONX 0914 (formerly PR-957)

While the majority of cell types in the body express the standard form of the proteasome (constitutive proteasome), cells of the immune system express the immunoproteasome, a unique form of the proteasome in which the three catalytic subunits differ from those of the standard proteasome. An immunoproteasome-specific inhibitor may have the potential to selectively target proteasome function in immune cells while exhibiting minimal effects on the proteasome in other tissues.

ONX 0914 was designed to be a potent inhibitor of the immunoproteasome with minimal cross-reactivity for the constitutive proteasome. Recent evidence suggests that the immunoproteasome regulates the production of several inflammatory cytokines, including Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), IL-17, and IL-23. In animal models of rheumatoid arthritis and lupus, ONX 0914 blocked progression of disease at well tolerated doses. Further preclinical studies are underway to evaluate the potential clinical applications of ONX 0914 in the treatment of autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease and lupus.