Targeted Protein Degradation Chemical Probes

Abstract

Chemical probes are invaluable tools in both fundamental and applied biological research, representing important reagents to support the unbiased interpretation of biological experiments necessary for rigorous preclinical target validation in drug discovery programmes. Targeted protein degradation stands out from classical pharmacology with unique features to develop high-quality chemical probes capable of destroying their targets, instead of modulating their activity. In addition to revalidating known targets and understanding the new biological outcomes of selective chemical degradation, the development of completely novel probes through proteolysis-targeting chimera (PROTAC) molecules or molecular glues can provide access to systems or functions that remain untapped for drug discovery. This chapter introduces the concept of targeted protein degradation, its particularities and its future impact on the finding of novel therapies. The technical advantages that targeted protein degradation offers in the development of high-quality chemical probes are discussed and exemplified.