Phosphorylation-driven targeted protein degradation of oncogenic β-catenin

Induced-proximity drugs are revolutionizing our ability to tackle previously considered undruggable targets. Here, we used a genome-scale approach to identify induced-proximity protein candidates that inhibit the central Wnt signalling effector beta-catenin in colorectal cancer cells.

While the identification of several E3 ubiquitin ligases validated our approach, we uncovered that inducing proximity to members of the Casein kinase I (CSNK1) family leads to beta-catenin degradation and inhibits the growth of colorectal cancer cells harbouring Wnt pathway mutations. We show that beta-catenin degradation induced by CSNK1 proximity is kinase activity- and proteasome-dependent. We propose that the formation of a neo-degron, through kinase recruitment, may expand the induced-proximity drug targeting strategies.