Recent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic

Proteolysis‐targeting chimeras (PROTACs), an emerging paradigm‐shifting technology, hijacks the ubiquitin‐proteasome system for targeted protein degradation. PROTACs induce ternary complexes between an E3 ligase and POI, and this induced proximity leads to polyUb chain formation on substrates and eventual proteasomal‐mediated POI degradation. PROTACs have shown great therapeutic potential by degrading many disease‐causing proteins, such as the androgen receptor and BRD4. The PROTAC technology has advanced significantly in the last two decades, with the repertoire of PROTAC targets increased tremendously. Herein, we describe recent developments of PROTAC technology, focusing on mechanistic and kinetic studies, pharmacokinetic study, spatiotemporal control of PROTACs, covalent PROTACs, resistance to PROTACs, and new E3 ligands. Over the past two decades, Proteolysis‐targeting chimeras (PROTACs) have been developed as a new approach for targeted protein degradation by hijacking the ubiquitin‐proteasome system. In this review, we describe recent PROTAC developments, focusing on mechanistic and kinetic studies, pharmacokinetic study, spatiotemporal control of PROTACs, covalent PROTACs, resistance to PROTACs, and new E3 ligands.