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.