Protein Degraders and Ternary Complexes

Unlocking the Potential: Targeted Protein Degradation in Drug Discovery

Targeted protein degradation has rapidly expanded as a promising approach in drug discovery, offering new possibilities for treating diseases that were once considered challenging or impossible to address. Two prominent classes of targeted protein degraders are Proteolysis-Targeting Chimeras (PROTAC® degraders) and molecular glues.

PROTAC® Degraders: Precision in Protein Degradation for Challenging Targets

Proteolysis-Targeting Chimeras (PROTAC® Degraders) are a class of small molecules designed to induce the selective degradation of specific proteins by harnessing the cell's natural protein degradation machinery. A PROTAC® degrader is a bivalent chemical probe that binds to both an E3 ligase and a protein of interest (POI) to induce the protein ubiquitination and subsequent degradation by the proteasome. 

This strategy enables the precise and selective degradation of target proteins that are difficult or impossible to inhibit using traditional methods. By harnessing the inherent process of protein degradation within cells, PROTAC® degraders offer a highly specific mechanism to eliminate target proteins. By understanding the structural details obtained from cryo-EM studies, structural biologists can optimize PROTAC® degrader design and enhance their efficacy and specificity, paving the way for the development of novel therapeutics. Encouragingly, preclinical studies are already demonstrating the potential of PROTAC® degraders as a therapeutic avenue for diverse diseases, including cancer, neurodegenerative disorders, and viral infections.

The Potential of Molecular Glues in Targeted Drug Interventions

Molecular glues are monovalent small molecules that promote novel protein-protein interactions leading to POI ubiquitination and subsequent proteasome degradation. Molecular glues consist of a small molecule capable of binding to distinct sites on two separate proteins, leading to changes in the structure or function of the proteins. Elucidating the structures of molecular glue complexes provides valuable insights into the conformational changes and intermolecular interactions that occur upon binding. By visualizing these complexes with cryo-EM, structural biologists can understand the mechanisms of action of molecular glues and their potential applications in drug discovery. Molecular glues offer a novel avenue for selectively activating or inhibiting these vital interactions, opening new possibilities for therapeutic interventions in a wide range of diseases.