Discovery of Novel Potent and Safe Immunoproteasome Inhibitors with Bridged Ring for Anti-Inflammatory Therapy.

Current clinical proteasome inhibitors suffer from nonselective pan-inhibition, leading to severe toxicity. Selective immunoproteasome inhibition offers a safer therapeutic strategy for autoimmune diseases. However, the inadequate LMP7/β5 selectivity of existing immunoproteasome inhibitors still lead to potential clinical side effects. To overcome this limitation, we designed and synthesized a series of novel immunoproteasome inhibitors featuring a bridged ring. The optimal compound A33 exhibited potent LMP7 inhibitory activity with >100-fold selectivity over β5 at the cellular level, along with ancillary activity against LMP2/MECL-1. Remarkably, A33 showed excellent anti-inflammatory effects in a mouse model of arthritis, and a favorable safety profile in toxicological studies, with reduced hepatotoxicity and hematotoxicity. Critically, we established a direct correlation between high LMP7/β5 selectivity and diminished systemic toxicity. In addition, A33 had favorable pharmacokinetic characteristics both in vitro and in vivo. These attractive drug-like properties establish A33 as a promising preclinical candidate compound with optimized selectivity and improved safety profile that merit further investigation.