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

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 <b>5c</b> 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, <b>5c</b> demonstrated good efficacy in an intragastrically administered mouse model of osteoporosis. Mechanistically, <b>5c</b> inhibited RANKL-induced osteoclastogenesis by activating Nrf2 signaling pathway. <b>5c</b> 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.