Advances in molecular glues: exploring chemical space and design principles for targeted protein degradation

• Low-molecular-weight molecular glue degraders employ a distinct mode of action that leverages ubiquitination and subsequent protein degradation. • Molecular glues possess attractive physicochemical properties, making them promising candidates for therapeutic development. • Biophysical, cell-based and in silico screening methods are used to explore extensive chemical space. • Partnerships between big pharma and start-ups drive the development of potentially transformative therapies for various novel targets. The discovery of the E3 ligase cereblon (CRBN) as the target of thalidomide and its analogs revolutionized the field of targeted protein degradation (TPD). This ubiquitin-mediated degradation pathway was first harnessed by bivalent degraders. Recently, the emergence of low-molecular-weight molecular glue degraders (MGDs) has expanded the TPD landscape, because MGDs operate via the same mechanism while offering attractive physicochemical properties that are consistent with small-molecule therapeutics. This review delves into the discovery and advancement of MGDs, with case studies on cyclin K and the zinc finger protein IKZF2, highlighting the design principles, biological assays and therapeutic applications. Additionally, it examines the chemical space of molecular glues and outlines the collaborative efforts that are fueling innovation in this field.