Non-peptidic immunoproteasome β5i-selective inhibitor as potential treatment for idiopathic pulmonary fibrosis: Virtual screening, hit evolution and lead identification

• Published in: European journal of medicinal chemistry 2023-12, Vol.261, p.115856-115856, Article 115856
• Main Authors: Li, Yunxuan, Nan, Guanglei, Hou, Xianxin, Yan, Yechao, Yang, Yajun, Yang, Ying, Li, Ke, Xiao, Zhiyan
• Format: Article
• Language: English
• Subjects: Idiopathic pulmonary fibrosis; Immunoproteasome; Non-peptidic; Selective inhibitors; Virtual screening
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115856

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 μM against β5i was identified. Hit evolution based on the interaction mode of VS-7 proceeded, and a potent β5i inhibitor 54 (IC50 = 8.463 nM) with favorable subunit-selective profiles was obtained. Compound 54 also imposed significant effects on the release of TNF-α and IL-6, the transcriptional activity of NF-κB, as well as TGF-β1 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. [Display omitted] •A structure-based virtual screening identified the hit VS-7 as a β5i inhibitor.•A novel potent non-peptidic β5i inhibitor 54 was recognized by hit evolution.•54 exhibited favorable subunit-selective profiles.•54 showed significant anti-fibrotic effects both in vitro and in vivo.