Harnessing the Ubiquitin Proteasome System to Block Inflammation

Despite major advances in the past 20 years, chronic inflammatory and autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis represent areas of high clinical unmet need. Drivers of B-cell and T-cell activation and proliferation are often critical nodes for potential therapeutic intervention in these diseases. Traditional enzyme inhibitors are capable of blocking a portion of the disease-causing signal from critical proteins. However, these proteins more often work within a complex, and degradation of these proteins shuts down both the enzymatic function and the so-called scaffold function, resulting in more complete blockade of the disease-causing signal pathway.

NX-5948 (BTK degrader)

BTK plays a central role in B cells and myeloid cells by controlling downstream signaling of multiple receptors, including B cell receptor (BCR), Toll-like receptors (TLR), and Fc receptors. Specifically, as a critical component of BCR signaling, BTK governs B cell development, proliferation and antibody production. In macrophages, microglia, and mast cells, BTK controls activation processes, including the production of histamine through degranulation in mast cells and the secretion of inflammatory cytokines in macrophages. In brain-resident microglia, BTK controls microglia phagocytic ability, migration and cytokine production.

BTK targeting agents have emerged as treatment for a growing number of autoimmune disorders.

BTK participates in signaling pathways through both its kinase and scaffolding functions.

NX-5948, a brain-penetrant, potent, and selective BTK degrader, is predicted to exert a more complete elimination of signaling pathways compared to classical BTK inhibitors by targeting both the kinase and scaffolding functions of this important protein.

NX-0479/GS-6791 (IRAK4 degrader)