RANKL-IN-1 formate

RANKL-IN-1 formate is a selective receptor activator of nuclear factor-κB ligand inhibitor ligand ( RANKL ) inhibitor with a K D value of 7.6 μM. RANKL-IN-1 formate exhibits inhibitory activity and selectivity against osteoclastogenesis with an IC₅₀ value of 0.07 μM and SI of 82.57. RANKL-IN-1 formate binds directly to RANKL and blocks the RANKL-induced activation of the NF-κB and MAPK pathways. RANKL-IN-1 formate can be used for the research of metabolic disease, such as osteoporosis ^[1].

In Vivo, RANKL-IN-1 (Compound 19u) (0.313-1.25 μg/mL, 96 h) formate attenuated bone loss in zebrafish osteoporosis models^[1]. RANKL-IN-1 (0.5-2 mg/kg, p.o., every 2 days for 11 weeks) formate prevents systemic bone loss in ovariectomy-induced osteoporosis mice models^[1].

In Vitro, RANKL-IN-1 (Compound 19u) (50-400 nM, 4 days) formate shows no significant cytotoxicity in RAW264.7 cells^[1]. RANKL-IN-1 (50-400 nM, 4 days) formate inhibits RANKL-induced osteoclastogenesis without affecting osteoblast differentiation in RAW264.7 cells^[1]. RANKL-IN-1 (50-400 nM, 4 days) formate reduces RANKL-induced ROS levels and inhibits bone resorption in RAW264.7 cells^[1]. RANKL-IN-1 (50-400 nM, 4 days) formate inhibits the expression of proteins associated with RANKL-induced osteoclast differentiation in RAW264.7 cells^[1].

References:
[1]. Fu X, et al. Design, Synthesis, and Biological Evaluation of Heterocycle-Fused Celastrol Derivatives as Potent Antiosteoporosis Agents by Blocking RANKL-Induced Activation of the NF-κB and MAPK Signaling Pathways. J Med Chem. 2025 Aug 28;68(16):17678-17704.