PR-914

PR-914 (also known as BLX-914) is a potent and selective small-molecule inhibitor of the immunoproteasome, specifically targeting the **LMP7** (low molecular mass polypeptide 7, also known as PSMB8) subunit. Developed through a collaboration between **Onyx Pharmaceuticals** and **Biogen**, it belongs to the epoxyketone class of proteasome inhibitors. Unlike general proteasome inhibitors such as bortezomib, PR-914 preferentially targets the immunoproteasome, which is predominantly expressed in hematopoietic cells and upregulated during inflammatory responses. By inhibiting LMP7, PR-914 modulates the production of pro-inflammatory cytokines (including IL-6, IL-23, and TNF-α) and interferes with the differentiation of Th1 and Th17 cells. It has demonstrated significant therapeutic potential in preclinical models of various autoimmune and inflammatory disorders, including rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, by reducing tissue inflammation and autoantibody production without the broad cytotoxicity associated with constitutive proteasome inhibition.