Identification and selectivity profiling of small-molecule degraders via multi-omics approaches

Cell Chem Biol. 2021 Jul 15;28(7):1048-1060. doi: 10.1016/j.chembiol.2021.03.007. Epub 2021 Apr 2.

Abstract

The therapeutic modality of targeted protein degradation promises to overcome limitations of traditional pharmacology. Small-molecule degraders recruit disease-causing proteins to E3 ubiquitin ligases, prompting their ubiquitination and degradation by the proteasome. The discovery, mechanistic elucidation, and selectivity profiling of novel degraders are often conducted in cellular systems. This highlights the need for unbiased multi-omics strategies that inform on the functionally involved components. Here, we review how proteomics and functional genomics can be integrated to identify and mechanistically understand degraders, their target selectivity as well as putative resistance mechanisms.

Keywords: CRISPR-Cas9; PROTAC; functional genomics; molecular glue degrader; phenotypic screens; proteomics; target identification; targeted protein degradation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Proteolysis / drug effects
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Ubiquitin-Protein Ligases / antagonists & inhibitors*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / drug effects

Substances

  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Ubiquitin-Protein Ligases