Protein Degraders and Ternary Complexes

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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.

Graphic depiction of protein degrader PROTAC

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.

Graphic depiction of protein degrader molecular glue

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.

Decoding Protein Degraders with Cryo-EM

When it comes to multi-component complexes like PROTAC® degraders and molecular glues, cryo-EM offers unique advantages over X-ray crystallography (XRC) and Nuclear Magnetic Resonance (NMR). It allows for the observation of these complexes in their native state, revealing their different states and conformational changes. Cryo-EM can provide high-resolution structures, allowing researchers to better understand the intricate details of the interactions between the components and guiding rational design to improve degraders. Gaining structural insight of the degraders is essential for drug design to enhance therapeutic efficacy, improve drug targeting, and minimize adverse effects.

NanoImaging Services specializes in cryo-EM and provides valuable insights into the structural details of your targets, helping you advance your drug discovery efforts efficiently. Our state-of-the-art Thermo Fisher Scientific Glacios microscopes and Thermo Fisher Scientific Titan Krios microscopes enable us to obtain high-quality 2D classifications and 3D reconstructions of your PROTAC® degrader or molecular glue complexes. Schedule a meeting to explore the applications of cryo-EM for your multi-component complex and unlock the potential of targeted protein degraders in drug design and discovery.

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