The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K
Creators
- Mikołaj Słabicki1
- Zuzanna Kozicka2
- Georg Petzold3
- Yen-Der Li4
- Manisha Manojkumar1
- Richard D. Bunker3
- Katherine A. Donovan5
- Quinlan L. Sievers6
- Jonas Koeppel1
- Dakota Suchyta2
- Adam S. Sperling6
- Emma C. Fink6
- Jessica A. Gasser6
- Li R. Wang7
- Steven M. Corsello6
- Rob S. Sellar8
- Max Jan6
- Dennis Gillingham9
- Claudia Scholl10
- Stefan Fröhling11
- Todd R. Golub12
- Eric S. Fischer5
- Nicolas H. Thomä3
- Benjamin L. Ebert13
- 1. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Division of Translational Medical Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- 2. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; Faculty of Science, University of Basel, Basel, Switzerland
- 3. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- 4. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA
- 5. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- 6. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- 7. Broad Institute of MIT and Harvard, Cambridge, MA, USA
- 8. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Haematology, UCL Cancer Institute, University College London, London, UK
- 9. Faculty of Science, University of Basel, Basel, Switzerland
- 10. Division of Applied Functional Genomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- 11. Division of Translational Medical Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany
- 12. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA
- 13. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA
Description
Molecular glue compounds induce protein–protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets. 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 lines, we identify CR8—a cyclin-dependent kinase (CDK) inhibitor—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.
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