Product Overview
WAY 316606 is a selective small-molecule inhibitor of secreted frizzled-related protein-1 (sFRP-1) with EC50 value of 0.65 μM. The Wnt signaling has been proved to be a drug target of treatment for metabolic bone diseases such as osteoporosis. The studies found that loss-of-function mutations of Wnt antagonists caused increased bone formation and deletion of the Wnt antagonist sFRP-1 resulted in increased trabecular bone formation in aged mice. Thus small-molecule inhibitors of Wnt antagonist (sFRP-1) have been discovered and developed. WAY 316606 was screened out from a library of over 440,000 compounds by the cell-based assay measuring activation of Wnt signaling. It bound to sFRP-1 preferentially (Kd value of 0.08 μM) and inhibited the negative regulation of Wnt caused by sFRP-1.WAY 316606 has been proved to promote bone formation in an organ culture assay. WAY 316606 is a selective inhibitor of sFRP-1. It bound to sFRP-2 with 10-fold weaker affinity (Kd value of 1 μM). In a fluorescence polarization binding assay, WAY 316606 inhibited sFRP-1 with IC50 value of 0.5 μM. Although sequence of sFRP-1,-2 and-5 showed high identity, WAY 316606 selectively inhibited sFRP-1 against other two proteins. In the osteosarcoma U2-OS cell line used in a cell-based transient transfection and luciferase reporter assay, treatment of WAY 316606 dose-dependently increased Wnt-signaling with EC50 value of 0.65 μM. In an ex vivo assay using neonatal murine calvarium, treatment of WAY 316606 dose-dependently enhanced the osteoblast activity and stimulated bone formation up to 60% with EC50 value of 1 nM. Although WAY 316606 had good aqueous solubility and good stability, WAY 316606 exerted high plasma clearance (77 mL/min/kg) in rats, which suppressed sustained exposure and limited the compounds advancement as an orally administered anabolic bone agent.
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