A Novel Paradigm for Targeting Challenging Targets: Advancing Technologies and Future Directions of Molecular Glue Degraders.

Molecular glue degraders (MGDs) constitute a class of innovative therapeutic agents within the field of targeted protein degradation (TPD). In contrast to proteolysis-targeting chimeras (PROTACs), MGDs induce protein degradation by stabilizing the interaction between an E3 ubiquitin ligase and a target protein. They typically exhibit favorable drug-like characteristics, including lower molecular weight and enhanced bioavailability. Although their discovery was historically serendipitous, recent advances in high-throughput screening, bioinformatics, and artificial intelligence are enabling more systematic identification and optimization. To date, three MGD-based drugs have been approved for clinical use, with numerous candidates under active investigation. This review comprehensively traces the technological progression of MGDs from serendipitous discovery to the current era of rational design. We systematically introduce and critically evaluate strategies for discovering MGDs, accompanied by illustrative examples. Concurrently, we discuss the major challenges hindering the broader application of MGDs and propose potential approaches to address these issues. Finally, we outline prospective research directions in the field. This review aims to provide a holistic framework for understanding the past, present, and future of molecular glue degraders, underscoring their significant potential to reshape the landscape of drug discovery.