MSCA ITN UbiCODE 765445

Part of EU Open Research Repository
Published August 3, 2020 | Version v1
Journal article Open

Rational discovery of molecular glue degraders via scalable chemical profiling

Creators

  • 1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
  • 2. FMI Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland Faculty of Science, University of Basel, Basel, Switzerland
  • 3. Institute of Structural Biology, University of Bonn, Bonn, Germany
  • 4. FMI Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
  • 5. Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
  • 6. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

Description

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.

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Additional details

Funding

European Commission
UbiCODE - European Research Training to Decipher The Ub Code : identification of potential biomarkers and drug targets 765445