Haven't got a glue: Protein surface variation for the design of molecular glue degraders

Abstract

Molecular glue degraders are small, drug-like compounds that induce interactions between an E3 ubiquitin ligase and a target, which result in ubiquitination and subsequent degradation of the recruited protein. In recent years, serendipitous discoveries revealed that some preclinical and clinical compounds already work as molecular glue degraders, with many more postulated to destabilize their targets through indirect or yet unresolved mechanisms. Here we review strategies by which E3 ubiquitin ligases can be reprogrammed by monovalent degraders, with a focus on molecular glues hijacking cullin-RING ubiquitin ligases. We argue that such drugs exploit the intrinsic property of proteins to form higher-order assemblies, a phenomenon previously seen with disease-causing sequence variations. Modifications of the protein surface by a bound small molecule can change the interactome of the target protein. By inducing interactions between a ligase and a substrate, molecular glue degraders offer an exciting path for the development of novel therapeutics.