Accelerating the Discovery of Next-Generation Small-Molecule Protein Degraders

Currently, many pharma and biotech companies as well as academic laboratories are developing PROTAC programs to investigate whether induced protein degradation offers new insights into a protein's pharmacological utility and new treatment opportunities for their high-value therapeutic targets. Within this review, we aim to explain the complexities and empiricism inherent in designing proteolysis-targeting chimeras, which result in the synthesis of compound libraries for the discovery of lead molecules with degrader potential. Due to typically limited resources in exploratory projects or concept space, this required synthesis of large compound libraries to fully explore PROTAC options is a high barrier to overcome. Thus, we also comment on how to strategically choose which molecules to synthesize and how the use of commercial building blocks can accelerate the discovery of degraders. Additionally, we describe the available assays for profiling PROTACs.