Proteolysis targeting chimeras (protein degraders) represent an innovative approach in drug discovery, leveraging bifunctional molecules to promote targeted protein degradation by linking target proteins to E3 ubiquitin ligases. Despite their promise, the development of protein degraders poses significant challenges:
Physicochemical Properties: Protein degraders, with molecular weights between 900-1,100 Da and increased polar surface area, often exhibit poor cell permeability, metabolic instability, and low oral bioavailability.
Optimization Complexity: Designing effective linkers and ligands requires balancing stability, solubility, and binding efficiency, while simultaneously enhancing PK and PD profiles.