新規Nrf2活性化剤は、Keap1-Nrf2タンパク質間相互作用に直接干渉することにより、破骨細胞形成および卵巣摘出誘発骨量減少を抑制する

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.