E3 Ubiquitin Ligases as Molecular Machines and Platforms for Drug Development

Many essential biological processes are regulated through protein–protein interactions. Some natural and synthetic small-molecule compounds also operate through induced protein proximity. In particular, molecular glue degraders are small drug-like compounds that prompt or strengthen the dimerization between E3 ubiquitin ligases and target proteins, prompting the target ubiquitination and subsequent proteasomal degradation. This and other pharmacological strategies of targeted protein degradation hold the promise to overcome some limitations of traditional occupancy-based therapeutic modalities. In this chapter, we summarize our current understanding of protein destabilization by molecular glue degraders, with a special focus on the following: (i) the serendipitous discoveries of some clinical and preclinical compounds and (ii) the first examples of intentional discoveries. By inducing proximity to E3 ligases, molecular glue degraders open up an exciting avenue for the development of novel therapeutics against otherwise undruggable proteins.