Induced proximity-based therapeutic modalities

Proximity is a key component of nearly all regulatory pathways within biological systems. Over the past few decades, the rapid development of induced proximity modalities has allowed for therapeutic intervention beyond classical occupancy-driven pharmacology. These modalities comprise multispecific small molecules or biologic agents that co-opt native biological pathways by inducing an interaction between biomolecules. Small-molecule 'molecular glues' modify protein surfaces to induce non-native interactions or to stabilize existing protein-protein interactions. They have been in the clinic since the 1980s but have more recently been shown to enable targeted protein degradation or inhibition and have been rationally designed to achieve this. Early discoveries on molecular glues spearheaded the development of next-generation heterobifunctional modalities for targeted protein degradation, such as proteolysis-targeting chimeras, which are seeing early-stage clinical success. Here, we aim to survey the field of induced proximity with a focus on potential therapeutic applications. We discuss the emergence of novel approaches to control cellular processes beyond protein degradation, including post-translational modifications, cellular localization and transcriptional activation. Some of these approaches are showing preclinical efficacy in various disease models.