[PDF][PDF] Targeted protein degradation in cancers: Orthodox PROTACs and beyond

J Li, X Chen, A Lu, C Liang - The Innovation, 2023 - cell.com
J Li, X Chen, A Lu, C Liang
The Innovation, 2023cell.com
Targeted protein degradation (TPD) is emerging as a strategy to overcome the limitations of
traditional small-molecule inhibitors. Proteolysis targeting chimera (PROTAC) technology
can be used to target proteins by hijacking the ubiquitin–proteasome system. Conceptually,
PROTAC aims to target the" undruggable" majority of proteins in the human proteome.
Through constant exploration and optimization of PROTACs and the exploitation of other
TPD strategies over two decades, TPD has expanded from theoretical studies to clinical …
Targeted protein degradation (TPD) is emerging as a strategy to overcome the limitations of traditional small-molecule inhibitors. Proteolysis targeting chimera (PROTAC) technology can be used to target proteins by hijacking the ubiquitin–proteasome system. Conceptually, PROTAC aims to target the "undruggable" majority of proteins in the human proteome. Through constant exploration and optimization of PROTACs and the exploitation of other TPD strategies over two decades, TPD has expanded from theoretical studies to clinical strategies, with practical applications in oncological, immunological, and other diseases. In this review, we introduce the mechanisms, features, and molecular targets of orthodox PROTACs and summarize the PROTAC drugs under study as cancer therapeutics in clinical trials. We also discuss PROTAC derivatives and other TPD strategies, such as lysosome targeting chimera, autophagy targeting chimera, and molecular glue strategies. Collectively, the studies summarized herein support the full potential of TPD in the biomedical industry.
cell.com