Targeted protein degradation for cancer therapy.

Targeted protein degradation (TPD) aims at reprogramming the target specificity of the ubiquitin-proteasome system, the major cellular protein disposal machinery, to induce selective ubiquitination and degradation of therapeutically relevant proteins. Since its conception over 20 years ago, TPD has gained a lot of attention mainly due to improvements in the design of bifunctional proteolysis targeting chimeras (PROTACs) and understanding the mechanisms underlying molecular glue degraders. Today, PROTACs are on the verge of a first clinical approval and recent structural and mechanistic insights combined with technological leaps promise to unlock the rational design of protein degraders, following the lead of lenalidomide and related clinically approved analogues. At the same time, the TPD universe is expanding at a record speed with the discovery of novel modalities beyond molecular glue degraders and PROTACs. Here we review the recent progress in the field, focusing on newly discovered degrader modalities, the current state of clinical degrader candidates for cancer therapy and upcoming design approaches.