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

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

  • Eur J Med Chem. 2023 Dec 5:261:115856. doi: 10.1016/j.ejmech.2023.115856.
Yunxuan Li 1,  Guanglei Nan 2,  Xianxin Hou 2,  Yechao Yan 1,  Yajun Yang 2,  Ying Yang 2,  Ke Li 3,  Zhiyan Xiao 4
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
  • 2 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 3 NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 4 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
PMID: 37826934 DOI: 10.1016/j.ejmech.2023.115856
Abstract

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.

Keywords

Idiopathic pulmonary fibrosis; Immunoproteasome; Non-peptidic; Selective inhibitors; Virtual screening.

Figures
Products