A Versatile and Sustainable Multicomponent Platform for the Synthesis of Protein Degraders: Proof-of-Concept Application to BRD4-Degrading PROTACs

The use of small molecules to induce targeted protein
degradation
is increasingly growing in the drug discovery landscape, and protein
degraders have progressed rapidly through the pipelines. Despite the
advances made so far, their synthesis still represents a significant
burden and new approaches are highly demanded. Herein we report an
unprecedented platform that leverages the modular nature of both multicomponent
reactions and degraders to enable the preparation of highly decorated
PROTACs. As a proof of principle, our platform has been applied to
the preparation of potential BRD4-degrading PROTACs, resulting in
the discovery of a set of degraders endowed with high degradation
efficiency. Compared to the existing methods, our approach offers
a versatile and cost-effective means to access libraries of protein
degraders and increase the chance of identifying successful candidates.