A Novel Nrf2 Activator Suppresses Osteoclastogenesis and Ovariectomy-Induced Bone Loss by Directly Interfering Keap1-Nrf2 Protein-Protein Interaction

  • J Med Chem. 2026 Mar 12;69(5):5787-5810. doi: 10.1021/acs.jmedchem.5c03085.
Shengbin Huang  1 ,  Lele Yi  2 ,  Yichi Zhang  1 ,  Xiangrui Song  2 ,  Lingling Zhou  2 ,  Zhihao Yu  2 ,  Haojin Chen  2 ,  Wanying Jiang  2 ,  Yao Wu  2 ,  Xiaolong Ye  3 ,  Zhengcan Hu  2 ,  Weiwei Xue  3 ,  Zengqiang Song  2
Affiliations
  • 1. Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China.
  • 2. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 3. School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
PMID: 41757458 DOI: 10.1021/acs.jmedchem.5c03085
Abstract

Drug-targeting osteoclasts is a mainstream strategy to treat Osteoporosis. The marketed antiosteoporotic medications present various adverse side effects and limited clinical responses. Activating Nrf2 attenuates osteoclastogenesis, and it is considered as a promising strategy for Osteoporosis therapy. Currently, no Nrf2 activators have progressed to clinical trial for the treatment of Osteoporosis. In this work, a series of 5-selenyl-flavone were efficiently prepared, and their inhibitory effects on RANKL-induced osteoclastogenesis were tested. Compound 5c was identified as the most potent compound that suppressed osteoclast formation and resorption activity, and decreased the level of expression of osteoclast-specific genes and proteins in vitro. In addition, 5c demonstrated good efficacy in an intragastrically administered mouse model of Osteoporosis. Mechanistically, 5c inhibited RANKL-induced osteoclastogenesis by activating Nrf2 signaling pathway. 5c noncovalently bound to the Kelch domain of KEAP1, and disrupted Keap1-Nrf2 protein-protein interaction. Collectively, the present study identifies a new Nrf2 activator possessing antiosteoporotic activity.

Products