Wnt-C59,WntAntagonist

Wnt-C59 is a very potent and highly selective Wnt signaling antagonist with an IC₅₀ ~ 74 pM in the Wnt signaling reporter assay. It prevents palmitylation of Wnt proteins by Porcupine (a membrane-bound O-acyltransferase), thereby blocking Wnt protein secretion and activity. Wnt-C59 displayed good bioavailability as once daily oral administration and blocked progression of mammary tumors in MMTV-WNT1 transgenic mice model while downregulating Wnt/β-catenin target genes. Because Wnt-C59 exhibits much better potency and selectivity than the reported IWP series of Porcupine/Wnt inhibitors, it serves as the better Wnt pathway inhibitor for in vitro and in vivo studies.

How to Use:

• In vitro: Wnt-C59 was used at 0.1-0.2 µM to completely block Wnt protein secretion. When used at 0.5 µM, it can be used functionally replace the Dkk protein in many assay conditions.
• In vivo: Wnt-C59 was used to dose mice orally at 5-10 mg/kg once per day or 5 mg/kg twice per day.

Reference:

• 1.  Proffitt KD, et al. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. (2012) Cancer Res. In press.
• 2.  Chen D, et al. (N-(HETERO)ARYL,2-(HETERO)ARYL-SUBSTITUTED ACETAMIDES FOR USE AS WNT SIGNALING MODULATORS. PCT WO/2010/101849.
• 3.  Chen B, et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. (2009) Nat Chem Biol. 5(2):100-7.
• 4.  Dodge ME, et al. Diverse chemical scaffolds support direct inhibition of the membrane bound O-acyltransferase Porcupine. (2012) J Biol Chem. 287 (27), pp. 23246–23254
• 5.  Willems E, et al. Small-molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cell-derived mesoderm.  (2011) Circ Res.109(4):360-4.