Phosphorylation-driven Targeted Protein Degradation of Oncogenic β-catenin

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Abstract
Therapeutic strategies to inhibit the Wnt signalling pathway for cancer treatment have, so far, failed to advance to the clinic. Induced-proximity drugs are revolutionizing our ability to tackle targets previously considered undruggable. Here, we used an unbiased genome-scale approach to identify induced-proximity protein candidates that inhibit the central Wnt signalling effector β-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 β-catenin degradation and inhibits the growth of colorectal cancer cells harbouring Wnt pathway mutations. We show that β-catenin degradation induced by CSNK1 proximity is kinase activity- and proteasome-dependent. We propose that the formation of a neo-degron, through kinase recruitment, can expand induced-proximity drug targeting strategies.
Funding Information
  • Deutsche Forschungsgemeinschaft (533617596)
  • Canadian Institutes of Health Research (PJT-175160)

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