An engineered cereblon optimized for high throughput screening and molecular glue discovery

The untapped potential for the discovery of molecular glue substrates leaves huge potential for exciting developments in this field. Through simplification of CRBN production and optimization of multiple biophysics and biochemical assays to measure ternary complex formation, we hope to provide improved resources for the validation and characterization of CRBN-based degraders. We show this applicability here through development of the “Enamine CRBN focused IMiD library” of 4480-IMiD based derivatives and application of our CRBN construct in high-throughput screening for the discovery of next generation binders. Importantly, our CRBN-based assays also extend to the cellular context allowing further assessment of CRBN binder interactomes by mass spectrometry providing exciting tools for target validation and specificity profiling. Taken together, we believe combining our IMiD based chemical binding landscape and “binding first” interactome screening approach with existing protein degradation profiling tools will have high potential to accelerate the future discovery of next generation CRBN glue substrates and degrader molecules.