Molecular glues: enhanced protein-protein interactions and cell proteome editing

The druggable genome is limited by structural features that can be targeted by small molecules in disease-relevant proteins. While orthosteric and allosteric protein modulators have been well studied, they are limited to antagonistic/agonistic functions. This approach to protein modulation leaves many disease-relevant proteins as undruggable targets. Recently, protein-protein interaction modulation has emerged as a promising therapeutic field for previously undruggable protein targets. Molecular glues and heterobifunctional degraders such as PROTACs can facilitate protein interactions and bring the proteasome into proximity to induce targeted protein degradation. In this review, we discuss the function and rational design of molecular glues, heterobifunctional degraders, and hydrophobic tag degraders. We also review historic and novel molecular glues and targets and discuss the challenges and opportunities in this new therapeutic field.