Design and applications of novel hydrophobic CRBN binders

Cereblon (CRBN) molecular glue degraders engage target proteins through a shallow binding pocket, representing a promising strategy to expand the druggable proteome. However, a key challenge in the structure-based discovery of CRBN molecular glues lies in the conformational diversity induced at the CRBN-substrate interface. Different CRBN binders can modulate this interface in distinct ways, ultimately determining which substrate proteins are recruited and defining compound selectivity.In this study, we designed and identified several novel CRBN binders exhibiting excellent or acceptable binary binding affinities. Compared with previously reported CRBN ligands, our compounds possess unique structural features and enhanced hydrophobic properties. Derivatives based on these scaffolds enabled the construction of a CRBN molecular glue library that extends into previously unexplored, CRBN-biased chemical space. This library provides a high-quality toolbox to accelerate the discovery of new targets using the CRBN molecular glue degrader approach.