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 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.

靶向破骨细胞是治疗骨质疏松症的主流策略。目前已上市的抗骨质疏松药物存在多种不良反应，且临床疗效有限。激活核因子E2相关因子2（Nrf2）可抑制破骨细胞生成，被认为是骨质疏松症治疗的极具潜力的策略。截至目前，尚无Nrf2激活剂进入骨质疏松症治疗的临床试验阶段。本研究高效制备了一系列5-硒基黄酮类化合物，并测试了其对核因子κB受体活化因子配体（RANKL）诱导的破骨细胞生成的抑制活性。化合物5c被鉴定为活性最强的候选化合物，可在体外抑制破骨细胞形成与骨吸收活性，并降低破骨细胞特异性基因及蛋白的表达水平。此外，5c在灌胃给药的骨质疏松小鼠模型中展现出良好的治疗功效。机制研究表明，5c通过激活Nrf2信号通路抑制RANKL诱导的破骨细胞生成：5c可与Kelch样环氧氯丙烷相关蛋白1（Keap1）的Kelch结构域非共价结合，破坏Keap1-Nrf2蛋白-蛋白相互作用。综上，本研究发现了一种具备抗骨质疏松活性的新型Nrf2激活剂。