Small-Molecule Approaches to Targeted Protein Degradation

Abstract

Many essential biological processes are regulated through proximity, from membrane receptor signaling to transcriptional activity. The ubiquitin-proteasome system controls protein degradation, with ubiquitin ligases as the rate-limiting step. Ubiquitin ligases are commonly controlled at the level of substrate recruitment and, therefore, by proximity. There are natural and synthetic small molecules that also operate through induced proximity. For example, thalidomide is effective in treating multiple myeloma and functions as a molecular glue that stabilizes novel protein-protein interactions between a ubiquitin ligase and proteins not otherwise targeted by the ligase, leading to neo-substrate degradation. Emerging data on new degrader molecules have uncovered diverse mechanisms distinct from molecular glues, which often mirror the regulatory mechanisms that control substrate-ligase proximity in nature. In this review, we summarize our current understanding of biological and synthetic regulation of protein degradation and share our view on how these diverse mechanisms have inspired novel therapeutic directions.