Wnt signaling is required for direct multiple biological processes and also plays key roles in the pathogenesis of various diseases. Axin is a cytoplasmic protein which contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. Axin is a component of the β-catenin destruction complex required for regulating CTNNB1 levels through phosphorylation and ubiquitination, and modulating Wnt-signaling. In Wnt signaling, axin probably facilitates the phosphorylation of CTNNB1 and APC by GSK3B[3].
KY1220 specifically binds to the RGS domain of Axin, activates GSK3β via a conformational change enhancing β-catenin complex assembly, and subsequently degrade both β-catenin and Ras via proteasomal degradation[4]. The inhibitory IC50 of KY1220 on the Wnt/β-catenin pathway was 2.1 μM, and in HEK293 cells, both β-catenin and pan-Ras protein levels were reduced in a dose-dependent manner after treatment with KY1220 at the concentration of 5~50 μM[5]. The proliferation and transformation of HCT15, SW480, D-WT and D-MT colon cancer cells were efficiently inhibited after treatment with KY1220[5].
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