Progress on molecular glue degraders

In the field of targeted protein degradation (TPD) therapy, molecular glue degraders (MGDs) have attracted widespread attention in recent years due to their excellent druggability. MGDs can specifically recruit E3 ubiquitin ligases, thereby regulating the function of the ubiquitin-proteasome system. In this article we review the research progress on the discovery history and mechanism of action of existing MGDs from two aspects: First, we systematically summarize the mechanism by which MGDs assist E3 ubiquitin ligases in mediating the ubiquitination of substrate proteins, and elaborate in detail the complete process in which MGDs induce conformational changes in proteins and remodel intermolecular interaction interfaces, thereby effectively facilitating the specific binding between E3 ubiquitin ligases and target proteins, and finally triggering the subsequent ubiquitination cascade reaction; Second, we systematically discuss the development strategies of novel MGDs and the discovery methods for new substrate proteins, covering the innovative application of technologies such as high-throughput screening based on molecular libraries and chemical proteomics, as well as the development of data-driven substrate prediction models.