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

Abstract

Glycogen synthase kinase-3 beta (GSK-3 beta) appears to be ordinarily expressed, and functionally redundant in Wnt/ beta-catenin signaling. The Wnt proteins induce transduction of a cytoplasmic protein, Dishevelled (Dvl) which negatively modulates GSK-3 beta activity. CXXC5 is a negative modulator of the Wnt/beta-catenin signaling through the interaction with Dvl in the cytosol. This indicates that Wnt/beta-catenin signaling could be efficiently modulated by controlling GSK-3 beta and the CXXC5-Dvl interaction. In this study, we designed a series of indirubin-3 & PRIME;-oxime and indirubin-3'-alkoxime derivatives containing various functional groups at the 5-or 6-position (R-1) alongside alkyl or benzylic moieties at the 3'-oxime position (R-2). These activate Wnt signaling through inhibitions of both GSK-3 beta 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-3 beta 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-3 beta inhibitors.