Rewriting protein fate: emerging strategies for targeted protein degradation and associated challenges.

Abstract

Classical small-molecule drugs have traditionally relied on an occupancy-driven paradigm that requires tight and sustained binding to a well-defined pocket on the target protein. Targeted protein degradation (TPD) approaches have emerged to overcome the limitations of traditional pharmacology to promote the selective degradation of disease-associated proteins, harnessing the central proteostasis pathways in eukaryotic cells: the ubiquitin proteasome system and the autophagy-lysosomal machinery. Thus, TPD exploits the idea of reprogramming cellular proteostasis for therapeutic benefits, dictating the fate of the target protein by means of degrader molecules that induce proximity between a target protein and components of the degradation machineries. The present review gives an overview of the molecular mechanisms of cellular proteostasis and how they are exploited for drug discovery purposes through TPD strategies. We describe some of the most explored degrader modalities, such as molecular glues, proteolysis targeting chimeras, and lysosomal targeting chimeras, as well as new modalities of degraders, highlighting their major advantages and limitations, and discuss the challenges associated with their development, including ligand identification, target degradability, or the possibility for their rational design. Furthermore, we consider recent advances in the design of these degraders to potentially address those limitations. Together, these insights established TPD as a transformative pharmacological modality that revolutionized drug discovery campaigns since it expands the druggable proteome, offering numerous advantages over traditional drugs.

Abstract as supplied by the indexing source. © the authors / publisher.