Accessing three-branched high-affinity cereblon ligands for molecular glue and protein degrader design

The Petasis borono-Mannich reaction was employed for an alternative entry towards three-branched cereblon ligands. Such compounds are capabable of making multiple interactions with the protein surface and possess a suitable linker exit vector. The high-affinity ligands were used to assemble prototypic new molecular glues and proteolysis targeting chimeras (PROTACs) targeting BRD4 for degradation. Our results highlight the importance of multicomponent reactions (MCRs) in drug discovery and add new insights into the rapidly growing field of protein degraders.

Automated summary

In this study, the Petasis borono-Mannich reaction was used to synthesize three-branched cereblon ligands, which can interact with protein surfaces and have a suitable linker exit vector. The high-affinity ligands were used to create new molecular glues and PROTACs targeting BRD4 for degradation, providing insights into protein degraders and emphasizing the importance of multicomponent reactions (MCRs) in drug discovery.