Drug discovery: First rational strategy to find molecular glue degraders

Despite enormous efforts to advance traditional pharmacology approaches, more than three quarters of all human proteins remain beyond the reach of therapeutic development. Targeted protein degradation (TPD) is a novel approach that could overcome this and other limitations, and thus represents a promising therapeutic strategy. TPD is based on small molecules, generally called 'degraders,' which can eliminate disease-causing proteins by causing their destabilization. Mechanistically, these degrader drugs repurpose the cellular protein quality control system, tweaking it to recognize and eliminate harmful proteins. In detail, they re-direct members of the protein family of E3 ubiquitin ligases (E3s) towards the disease-causing target protein. This leads to a "molecular earmarking" of the harmful protein via a process called 'ubiquitination.' Subsequently, the ubiquitinated protein is recognized and degraded by the molecular machine called the proteasome, which serves as the cellular garbage disposal system.