Human sFRP-1 is a 35 kD protein consisting of 313 amino acids. It containa 2 distinct structural domains, a netrin domain, and a cysteine-rich domain (CRD). The later domain is homologous to the Fzd receptor. sFRP-1 is thought to interact with Wnt via the CRD domain in a competitive manner with the Fzd receptor. Thus sFRP-1 is a negative regulator or an antagonist of the Wnt signaling pathway. Increased expression of sFRP-1 in OB cells results in suppression of Wnt signaling, leading to decreased OB survival, activation, and differentiation. Conversely, deletion of the sFRP-1 gene in mice results in increased Wnt signaling. Thus, it leads to OB activation, proliferation, and differentiation resulting in increases in trabecular bone.
WAY 316606 is an inhibitor of the secreted protein sFRP-1, an endogenous antagonist of the secreted glycoprotein Wnt.
The EC50 of WAY-316606 for Wnt-Luciferase Activity from U2-OS Cells is 0.65 μM. WAY-316606 binds to secreted frizzled-related protein (sFRP)-1 inhibitor with a KD of 0.08 μM and inhibits sFRP-1 with an EC50 of 0.65 μM. It also binds to sFRP-2, albeit over 10 times weaker with a KD of 1 μM. Using a fluorescence polarization binding assay that employs a fluorescent probe compound and purified human sFRP-1 protein in a competitive-binding format. The IC50 for WAY-316606 is 0.5 μM.
WAY-316606 increases bone formation when tested in a neonatal murine calvarial assay. This compound increases total bone area up to 60% in a dose-dependent manner with an EC50 of about 1 nM. It has good aqueous solubility, moderate to low inhibition of cytochrome p450 isozymes (3A4, 2D6, 2C9). This compound also has good stability in rat and human liver microsomes (t1/2>60 min in each species). In female Sprague-Dawley rats, WAY-316606 exhibits high plasma clearance (77 mL/min/kg, greater than hepatic blood flow) following a single intravenous bolus dose (2 mg/kg), which results in a rapid decline of drug exposure in the plasma despite the route of administration.
In conclusion, WAY-316606 has the potential for the research of cancer disease.