Degrader Building Blocks for Targeted Protein Degradation

Targeted Protein Degradation

Targeted protein degradation is a novel strategy that uses small molecules to hijack endogenous proteolysis systems to degrade disease-relevant proteins. Reducing protein abundance in cells, phenotypes similar to gene-editing approaches (e.g. CRISPR-Cas9) can be achieved but with the advantages that come with small molecules. Not only is this of interest as a research tool to study the impact of selective protein knockdowns, but it has quickly been adopted by the global drug discovery community for its advantages over occupancy-based inhibition and drugging ~80% of proteins traditionally intractable to small molecules. Agents used in these approaches are called protein degraders, such as proteolysis-targeting chimeras (PROTAC^® degraders) or molecular glues.

Heterobifunctional protein degraders contain a target-binding warhead on one end and an E3 ubiquitin ligase-targeting ligand on the other, connected by a linker in the middle (Figure 1). When the degrader is applied, it recruits the target to the E3 ligase. Once in proximity of the E3 ligase, the target is polyubiquitinated, flagging it for degradation via the proteasome.^1-3

^{PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.}

Challenges for Protein Degrader Synthesis

The design of degraders is challenging as slight alterations in structure can alter ternary complex formation and subsequent degradation.⁴ The 3D model in Figure 2 based on PDB 5T35 illustrates the importance of careful design to achieve binding to two disparate proteins (the target and E3 ligase) and the establishment of a protein–protein interface. Even with advances in computational chemistry, degrader design is still largely an empirical process where researchers generate libraries of degraders, taking a modular approach to varying the ligands, linkers, and exit vectors, an intense upfront chemistry endeavor.^4,6

Streamlined Synthesis of Heterobifunctional Degrader Libraries

Our protein degrader building blocks are the easiest way to generate heterobifunctional degrader screening libraries from one starting target ligand to expedite degrader hit discovery. Within this building block collection that comprises all the components to construct degraders, our ligand–linker conjugates eliminate upfront synthetic steps, requiring only the chemistry to link a target ligand on the terminal functional group (Figure 3). Moreover, if the same terminal chemistry is selected, a chemist can simultaneously react 50+ ligand–linker conjugates with one starting target ligand in parallel to generate an initial screening library.