2. Academic Validation
  3. Rational discovery of molecular glue degraders via scalable chemical profiling

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.
Cristina Mayor-Ruiz 1,  Sophie Bauer  # 1,  Matthias Brand  # 1,  Zuzanna Kozicka 2 3,  Marton Siklos 1,  Hana Imrichova 1,  Ines H Kaltheuner 4,  Elisa Hahn 1,  Kristina Seiler 1,  Anna Koren 1,  Georg Petzold 2,  Michaela Fellner 5,  Christoph Bock 1 6,  André C Müller 1,  Johannes Zuber 5,  Matthias Geyer 4,  Nicolas H Thomä 2,  Stefan Kubicek 1,  Georg E Winter 7
Affiliations

Affiliations

  • 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.
  • 3 Faculty of Science, University of Basel, Basel, Switzerland.
  • 4 Institute of Structural Biology, University of Bonn, Bonn, Germany.
  • 5 Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria.
  • 6 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
  • 7 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. gwinter@cemm.oeaw.ac.at.
  • # Contributed equally.
PMID: 32747809 DOI: 10.1038/s41589-020-0594-x
Abstract

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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