Targeted protein degradation in drug development: Recent advances and future challenges

Eur J Med Chem. 2023 Dec 5:261:115839. doi: 10.1016/j.ejmech.2023.115839. Epub 2023 Sep 27.

Abstract

Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of dosing, side effects and targeting "undruggable" proteins. Targeted degraders can theoretically bind any nook or cranny of targeted proteins to drive degradation. This offers convenience versus the small-molecule inhibitors that must function in a well-defined pocket. The degradation process depends mainly on two cell self-destruction mechanisms, namely the ubiquitin-proteasome system and the lysosomal degradation pathway. Various TPD strategies (e.g., proteolytic-targeting chimeras, molecular glues, lysosome-targeting chimeras, and autophagy-targeting chimeras) have been developed. These approaches hold great potential for targeting dysregulated proteins, potentially offering therapeutic benefits. In this article, we systematically review the mechanisms of various TPD strategies, potential applications to drug discovery, and recent advances. We also discuss the benefits and challenges associated with these TPD strategies, aiming to provide insight into the targeting of dysregulated proteins and facilitate their clinical applications.

Keywords: Drug discovery; Dysregulated protein; Lysosome-targeting chimera; Proteolytic-targeting chimera; Targeted protein degradation.

Publication types

  • Systematic Review
  • Review

MeSH terms

  • Autophagy*
  • Drug Discovery
  • Lysosomes
  • Proteasome Endopeptidase Complex*
  • Proteolysis

Substances

  • Proteasome Endopeptidase Complex