Targeted protein degradation (TPD) is an emerging therapeutic strategy that hijacks the cellular recycling machinery to degrade and remove disease causing proteins. The E3 ligase Cereblon (CRBN) is the central player for this process. Small molecule drugs recruit disease relevant proteins to the CRBN surface, which are then marked for degradation and removed by the cells.

Access to high quality protein tools and biochemical assays that allow us to understand these complex interactions are a major bottleneck, preventing the development of these promising therapeutic ideas.

In their new publication in Cell Chemical Biology, IBC2 director Ivan Đikić’s lab and Merck KGaA, collaborated with Enamine Ltd, the Nowak Lab, the Langer Lab and iBET and to apply protein engineering methods to remove portions of the CRBN protein, leaving behind stable regions essential to engage disease relevant targets. IBC2 director Ivan Đikić highlights, “this is a cost-efficient method to produce ‘easy to handle’ versions of the CRBN protein, which will greatly accelerate this challenging area of small molecule drug development.”

The optimized CRBN is highly active in high-throughput drug screening assays and was used by the team to screen large chemical libraries (developed by Enamine) and to establish new chemo-proteomic assays that allow for the quick and easy determination of interactomes in a cellular environment. IBC2 researcher Henry Bailey explains: “We were able to successfully use the newly developed CRBN to create exciting new assays to screen for potential new degradation targets of CRBN and to understand the binding specificity of degrader molecules in the cell.”

Alessio Ciulli’s lab at the Centre for Targeted Protein Degradation (Dundee, UK) recently optimized the CRBN-midi protein for structure determination, allowing atomic details for known binders. Coupling these assays with existing methods in TPD provides an exciting tool kit for future degrader discoveries.