Two forms are the constitutive proteasome, expressed by the majority of cells in the body, and the immunoproteasome, expressed in cells derived from the bone marrow, including T-cells and B-cells, two types of white blood cells.
In addition, this work includes structural analysis of the binding of ONX 0914, a selective inhibitor of the immunoproteasome being developed by Onyx, to proteasome active sites. These findings demonstrate the selectivity of ONX 0914, Onyx's proprietary compound, and support the rational design of new immunoproteasome-specific and dual-targeting inhibitors for the potential treatment of autoimmune disorders and cancer. The article is titled "Immuno- and Constitutive Proteasome Crystal Structures Reveal Differences in Substrate and Inhibitor Specificity."
"This research demonstrates the molecular basis of the selectivity of ONX 0914 for the immunoproteasome and highlights its potential as a treatment for autoimmune disorders, such as rheumatoid arthritis and lupus. Selective inhibition of the immunoproteasome may provide anti-inflammatory activity while having a minimal effect on the proteasome in other tissues or on normal immune system function," said Christopher J. Kirk, Ph.D., Vice President of Research at Onyx Pharmaceuticals.
Authors included Drs. Eva Huber, Wolfgang Heinemeyer and Michael Groll of the Center for Integrated Protein Science at the Technical University in Munich, Germany; Drs. Michael Basler, Ricarda Schwab and Marcus Groettrup of the University of Constance in Konstanz, Germany; and Dr. Christopher Kirk of Onyx Pharmaceuticals where ONX 0914 is being developed.
About ONX 0914 ONX 0914, currently in preclinical development, is a highly selective immunoproteasome inhibitor with potential treatment applications in autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease and lupus.
The proteasome is an intracellular complex present in most cells that mediates the degradation of intracellular proteins, including key components of pathways that contribute to cancer cell growth and immune signaling. It is a proven and validated target for therapeutic intervention in oncology, but the side effect profiles of existing inhibitors have restricted the potential of this target for therapeutic intervention in autoimmune diseases. While the majority of cell types in the body express the standard form of the proteasome called the constitutive proteasome, cells of the immune system express a unique form of the proteasome called the immunoproteasome. An immunoproteasome-specific inhibitor may have the potential to selectively target proteasome function in immune cells, with minimal effects on the proteasome in other cells.
ONX 0914 was specifically 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-a (TNF-a), Interleukin-6 (IL-6), IL-17, and IL-23. In preclinical models of rheumatoid arthritis and lupus, ONX 0914 blocked progression of these diseases and was generally well-tolerated. Preclinical studies are underway to evaluate the potential of ONX 0914 in the treatment of a range of autoimmune disorders.