Indirubin-3'-alkoxime derivatives for upregulation of Wnt signaling through dual inhibition of GSK-3ß and the CXXC5-Dvl interaction.

ABSTRACT

Glycogen synthase kinase-3ß (GSK-3ß) appears to be ordinarily expressed, and functionally redundant in Wnt/ß-catenin signaling. The Wnt proteins induce transduction of a cytoplasmic protein, Dishevelled (Dvl) which negatively modulates GSK-3ß activity. CXXC5 is a negative modulator of the Wnt/ß-catenin signaling through the interaction with Dvl in the cytosol. This indicates that Wnt/ß-catenin signaling could be efficiently modulated by controlling GSK-3ß 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-3ß 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-3ß and the CXXC5-Dvl interaction could be an appropriate approach towards safely and efficientlyactivating Wntsignaling. Thus, dual-targeting inhibitors are potentially better candidates for efficient activation ofWntsignaling compared to GSK-3ß inhibitors.