Non-peptidic immunoproteasome 85i-selective inhibitor as potential treatment for idiopathic pulmonary fibrosis: Virtual screening, hit evolution and lead identification

The immunoproteasome has emerged as a potential therapeutic target for idiopathic pulmonary fibrosis (IPF). We report herein our efforts to discover novel non-peptidic immunoproteasome inhibitors as potential treatment for IPF. A structure-based virtual screening was initially performed and the hit compound VS-7 with an IC50 of 9.437 mu M against 85i was identified. Hit evolution based on the interaction mode of VS-7 proceeded, and a potent 85i inhibitor 54 (IC50 = 8.463 nM) with favorable subunit-selective profiles was obtained. Compound 54 also imposed significant effects on the release of TNF-alpha and IL-6, the transcriptional activity of NF-kappa B, as well as TGF-81 induced fibroblast proliferation, activation and collagen synthesis. Notably, when administered at 30 mg/kg in a bleomycin-induced IPF mouse model, compound 54 showed anti-fibrotic effects comparable to the clinical drug nintedanib. The results suggest that selective inhibition of immunoproteasome could be an effective approach to treat IPF.