Covalent Molecular Glues: Mechanisms, Design Principles, and Emerging Therapeutic Opportunities in Targeted Protein Degradation

Targeted protein degradation (TPD) has revolutionized modern drug discovery by enabling the catalytic and selective removal of disease-driving proteins that are beyond the reach of traditional inhibition. Among emerging TPD modalities, covalent molecular glues represent a rapidly expanding class of small molecules that combine the interface-inducing behavior of classical molecular glues with the durable target engagement of covalent chemistry. These compounds initiate non-covalent recognition events and subsequently form selective covalent bonds with nucleophilic residues, stabilizing weak or non-native protein-protein interactions to promote ubiquitination or functional modulation. This review provides a comprehensive overview of covalent molecular glues, encompassing natural products, synthetic scaffolds, warhead strategies, and mechanistic foundations governing covalent anchoring, cooperativity, and neo-interface formation. Key examples-including DCAF16-, FBXO22-, UBE2D-, and 14-3-3σ-targeting glues-highlight their capacity to engage challenging protein surfaces, remodel ubiquitin ligase specificity, and degrade previously undruggable substrates such as transcription factors and KRAS G12C. We further discuss technological advances driving rational discovery, including covalent fragment-based screening, electrophile library profiling, chemoproteomics, and AI-guided covalent docking. Finally, we summarize therapeutic opportunities across oncology, neurodegeneration, and immunomodulation, while outlining current challenges and future directions needed to expand the ligase landscape, improve safety, and achieve predictive design. Covalent molecular glues are poised to become a foundational modality in next-generation precision therapeutics.