Direct-to-Biology Strategy Accelerates CRBN-Targeting Molecular Glue Degrader Discovery

Molecular glue degraders (MGD), a new drug modality that utilizes the natural proteasomal degradation machinery in cells for target protein degradation, is drawing great attraction from the pharmaceutical industry in recent years. However, the pace of MGD molecule discovery can be largely limited by the low throughput of conventional chemical synthesis and tedious purification processes. It is long-awaited to develop a new screening strategy to release the potentials of high-throughput chemical synthesis while organically integrating compound library construction with assay testing. Here, by leveraging the mild reaction conditions of amide coupling, we demonstrate the implementation of "Direct-to-Biology" (D2B) strategy for Cereblon (CRBN)-targeting MGD discovery with in-plate microscale high-throughput library construction directly followed by cellular HiBiT-based target protein degradation assay screening without purification. Our results indicate that the crude D2B compound mixtures can show comparable efficacy and potency as their purified counterparts. And by systematically integrating chemistry with biology, we can significantly accelerate the pace of MGD discovery.