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.