Rational discovery of molecular glue degraders via scalable chemical profiling

Nat Chem Biol. 2020 Nov;16(11):1199-1207. doi: 10.1038/s41589-020-0594-x. Epub 2020 Aug 3.


Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been serendipitous, thus hampering broad translational efforts. Here, we describe a scalable strategy toward glue degrader discovery that is based on chemical screening in hyponeddylated cells coupled to a multi-omics target deconvolution campaign. This approach led us to identify compounds that induce ubiquitination and degradation of cyclin K by prompting an interaction of CDK12-cyclin K with a CRL4B ligase complex. Notably, this interaction is independent of a dedicated substrate receptor, thus functionally segregating this mechanism from all described degraders. Collectively, our data outline a versatile and broadly applicable strategy to identify degraders with nonobvious mechanisms and thus empower future drug discovery efforts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / metabolism*
  • Cyclins / metabolism*
  • Dose-Response Relationship, Drug
  • Doxycycline / pharmacology*
  • Drug Evaluation, Preclinical
  • Gene Expression Regulation
  • Humans
  • Hydrazines / chemistry*
  • Indoles / chemistry*
  • Molecular Structure
  • Protein Binding
  • Protein Conformation
  • Protein Processing, Post-Translational / drug effects
  • Proteolysis / drug effects*
  • Retinoblastoma-Binding Protein 7 / metabolism*
  • Small Molecule Libraries / chemistry
  • Structure-Activity Relationship
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / drug effects


  • Acetamides
  • Anti-Bacterial Agents
  • CCNK protein, human
  • Cyclins
  • Hydrazines
  • Indoles
  • RBBP7 protein, human
  • Retinoblastoma-Binding Protein 7
  • Small Molecule Libraries
  • Ubiquitin-Protein Ligases
  • CDK12 protein, human
  • Cyclin-Dependent Kinases
  • Doxycycline