Advances in molecular glue degraders for targeted protein degradation: Focus on NEK7, WEE1, CDK2, GSPT1 and VAV1.

Molecular glues (MGs), a class of small-molecule degraders, exhibit drug-like properties that generally conform to Lipinski's rule of five, while uniquely mediating the stabilization or induction of protein-protein interactions. By altering the surface properties of either target proteins or E3 ligases, MGs promote the formation of a ternary complex comprising the MG, an E3 ligase, and a target protein. This interaction facilitates the polyubiquitination and subsequent degradation of the target protein via the ubiquitin-proteasome system. Owing to its distinctive mechanism of action and broad therapeutic potential, MG is offering novel approaches to disease treatment. This review summarizes recent advances in MGs targeting NIMA-related kinase 7 (NEK7), WEE1, CDK2, GSPT1 and VAV1, emphasizing the rational design, benefits, and potential limitations, highlighting rational design principles, advantages, and current limitations including challenges in achieving selectivity and rational design that provide critical insights for enhancing MG efficacy. These developments are crucial for advancing the application and optimization of molecular glues targeting NEK7, WEE1, CDK2, GSPT1 and VAV1.