Indirubin-3′-alkoxime derivatives for upregulation of Wnt signaling through dual inhibition of GSK-3β and the CXXC5-Dvl interaction

Glycogen synthase kinase-3β (GSK-3β) appears to be ordinarily expressed, and functionally redundant in Wnt/β-catenin signaling. The Wnt proteins induce transduction of a cytoplasmic protein, Dishevelled (Dvl) which negatively modulates GSK-3β activity. CXXC5 is a negative modulator of the Wnt/β-catenin signaling through the interaction with Dvl in the cytosol. This indicates that Wnt/β-catenin signaling could be efficiently modulated by controlling GSK-3β and the CXXC5-Dvl interaction. In this study, we designed a series of indirubin-3′-oxime and indirubin-3′-alkoxime derivatives containing various functional groups at the 5- or 6-position (R₁) alongside alkyl or benzylic moieties at the 3′-oxime position (R₂). These activate Wnt signaling through inhibitions of both GSK-3β and the CXXC5-Dvl protein–protein interaction, in addition, the improvement of pharmacological properties. The potent activity profiles of the synthesized compounds suggested that dual inhibition of GSK-3β and the CXXC5-Dvl interaction could be an appropriate approach towards safely and efficiently activating Wnt signaling. Thus, dual-targeting inhibitors are potentially better candidates for efficient activation of Wnt signaling compared to GSK-3β inhibitors.