A Reliable and Sustainable Multicomponent Access to Protein Degraders

Abstract

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 urgently 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 and hydrophobic tag-mediated degraders. 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 clinical candidates.

Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One

“…However, multitarget PROTACs based on two different POI ligands ( Figure 5 A) are more challenging than classical PROTACs in terms of (i) synthesis and (ii) PK profiles, due to their inherently higher structural complexity. As for point (i), a toolbox for PROTAC modular synthesis 67 and a “click chemistry platform” 68 have already proven effective for accessing libraries of PROTACs. In addition, branched functionalization sites with controlled orientation have been reported, 69 clearly highlighting the ongoing interest of the scientific community to expand the field in this direction.…”