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The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K.
Journal article

The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K.

  • Słabicki M Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Kozicka Z Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Petzold G Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Li YD Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Manojkumar M Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bunker RD Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Donovan KA Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Sievers QL Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Koeppel J Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Suchyta D Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Sperling AS Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Fink EC Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gasser JA Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wang LR Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Corsello SM Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Sellar RS Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Jan M Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gillingham D Faculty of Science, University of Basel, Basel, Switzerland.
  • Scholl C Division of Applied Functional Genomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • Fröhling S Division of Translational Medical Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • Golub TR Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Fischer ES Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Thomä NH Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. nicolas.thoma@fmi.ch.
  • Ebert BL Broad Institute of MIT and Harvard, Cambridge, MA, USA. benjamin_ebert@dfci.harvard.edu.
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  • 2020-06-05
Published in:
  • Nature. - 2020
Cell Line, Tumor
Cyclin-Dependent Kinases
Cyclins
DNA-Binding Proteins
Humans
Models, Molecular
Proteasome Endopeptidase Complex
Protein Binding
Proteolysis
Purines
Pyridines
Small Molecule Libraries
Ubiquitination
English Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation1. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets2. They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines3-5, we identify CR8-a cyclin-dependent kinase (CDK) inhibitor6-as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues.
Language
  • English
Open access status
green
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/277547
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