Chasing molecular glue degraders: screening approaches

Abstract

Protein-protein interactions (PPIs) govern all biological processes. Some small molecules modulate PPIs through induced protein proximity. In particular, molecular glue degraders are monovalent compounds that orchestrate interactions between a target protein and an E3 ubiquitin ligase, prompting the proteasomal degradation of the former. This and other pharmacological strategies of targeted protein degradation (e.g. proteolysis-targeting chimeras - PROTACs) overcome some limitations of traditional occupancy-based therapeutics. Here, we provide an overview of the "molecular glue" concept, with a special focus on natural and synthetic inducers of proximity to E3s. We then briefly highlight the serendipitous discoveries of some clinical and preclinical molecular glue degraders, and discuss the first examples of intentional discoveries. Specifically, we outline the different screening strategies reported in this rapidly evolving arena and our thoughts on future perspectives. By mastering the ability to influence PPIs, molecular glue degraders can induce the degradation of unligandable proteins, thus providing an exciting path forward to broaden the targetable proteome.