Innovative, combinatorial and high-throughput approaches to degrader synthesis

Chem Soc Rev. 2024 May 20;53(10):4838-4861. doi: 10.1039/d3cs01127e.

Abstract

Targeted protein degraders such as PROTACs and molecular glues are a rapidly emerging therapeutic modality within industry and academia. Degraders possess unique mechanisms of action that lead to the removal of specific proteins by co-opting the cell's natural degradation mechanisms via induced proximity. Their optimisation thus far has often been largely empirical, requiring the synthesis and screening of a large number of analogues. In addition, the synthesis and development of degraders is often challenging, leading to lengthy optimisation campaigns to deliver candidate-quality compounds. This review highlights how the synthesis of degraders has evolved in recent years, in particular focusing on means of applying high-throughput chemistry and screening approaches to expedite these timelines, which we anticipate to be valuable in shaping the future of degrader optimisation campaigns.

Publication types

  • Review

MeSH terms

  • Combinatorial Chemistry Techniques*
  • High-Throughput Screening Assays*
  • Proteins / chemistry
  • Proteins / metabolism
  • Proteolysis
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry