Molecular glues for targeted protein degradation: a new paradigm beyond conventional protacs

Targeted protein degradation (TPD) represents a transformative therapeutic modality that exploits the intracellular ubiquitin-proteasome system (UPS) to selectively eliminate disease-causing proteins. Within the TPD landscape, two distinct mechanistic classes have emerged: Proteolysis-Targeting Chimeras (PROTACs), bifunctional heterodimeric molecules that bridge a protein of interest (POI) with an E3 ubiquitin ligase via a chemical linker; and molecular glues, typically monofunctional small molecules that stabilize neo-substrate recruitment on the surface of an E3 ligase through induced protein-protein interaction interfaces. While PROTACs offer unparalleled modularity and rational design accessibility, molecular glues, exemplified by the immunomodulatory drug (IMiD) class and next-generation cereblon E3 ligase modulators (CELMoDs), have accumulated the most robust clinical validation in the field, including multiple FDA and EMA approvals for hematological malignancies. This review provides a comprehensive and critical comparative analysis of both paradigms, covering mechanism of action at atomic resolution, structural basis of E3 ligase recruitment, pharmacological properties, resistance mechanisms, and clinical development status. This review position as a compelling and clinically superior paradigm for targeted protein degradation, while acknowledging the complementary strengths that both classes offer to the broader TPD therapeutic landscape.