Discovery of Propionic Acid Derivatives with a 5-THIQ Core as Potent and Orally Bioavailable Keap1-Nrf2 Protein-Protein Interaction Inhibitors for Acute Kidney Injury

  • J Med Chem. 2024 Oct 10. doi: 10.1021/acs.jmedchem.4c01687.
Zeyu Shi  1 ,  Yong Zhang  1 ,  Xinyu Wang  1 ,  Jingshu Tang  1 ,  Yuying Kang  1 ,  Jiahuan Hu  1 ,  Li Li  1 ,  Beibei Yang  1 ,  Si Chen  1 ,  Qiong Xiao  1 ,  Jiaqi Lan  1 ,  Jinping Hu  1 ,  Ying Peng  1 ,  Dali Yin  1
Affiliations
  • 1. Department of Medicinal Chemistry, State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
PMID: 39388678 DOI: 10.1021/acs.jmedchem.4c01687
Abstract

KEAP1 plays a crucial role in regulating the Nrf2-mediated cytoprotective response and is increasingly targeted for oxidative stress-related diseases. Using small molecules to disrupt the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as a new strategy for developing Nrf2 activators. Through extensive structure-activity relationship studies, we identified compound 56, which features a unique 5-tetrahydroisoquinoline scaffold and acts as a potent inhibitor of the Keap1-Nrf2 PPI. Compound 56 exhibited significant inhibitory activity (IC50 = 16.0 nM) and tight KEAP1 binding affinity (Kd = 3.07 nM), along with acceptable oral bioavailability (F = 20%). Notably, 56 enhanced antioxidant defenses in HK-2 renal tubular epithelial cells and significantly reduced plasma creatinine and blood urea nitrogen levels in acute kidney injury (AKI) mice. These findings collectively position compound 56 as a promising candidate for the treatment of AKI.

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