From Degraders to Molecular Glues: New Ways of Breaking Down Disease‐Associated Proteins

Targeted protein degradation is becoming a weapon of choice against targets considered heretofore "undruggable." Whereas most small molecules inhibit a protein by blocking its active site, degraders or proteolysis-targeting chimeras (PROTACs) and other protein destabilizers harness the cell's own recycling machinery to remove the entire protein. It is an exciting time for this new technology that currently transitions from laboratory to clinic. In this book chapter, we will give a brief overview starting from the first to the latest generation of degraders that are just hitting the clinic and discuss their potential as a new therapeutic modality. Furthermore, we will highlight the latest developments in this rapidly evolving area and outline learnings for design and synthesis of degraders. Finally, we will discuss future perspectives and the potential next generation of degraders as well as related technologies, which harness the cell's proteasomal machinery, such as molecular glue-like degraders or monovalent degraders.