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

Mikołaj Słabicki, Zuzanna Kozicka, Georg Petzold, Yen- Der Li, Manisha Manojkumar, Richard D. Bunker, Katherine A. Donovan, Quinlan L. Sievers, Jonas Koeppel, Dakota Suchyta, Adam S. Sperling, Emma C. Fink, Jessica A. Gasser, Li R. Wang, Steven M. Corsello, Rob S. Sellar, Max Jan, Dennis Gillingham, Claudia Scholl, Stefan Fröhling, Todd R. Golub, Eric S. Fischer, Nicolas H. Thomä () and Benjamin L. Ebert ()
Additional contact information
Mikołaj Słabicki: Broad Institute of MIT and Harvard
Zuzanna Kozicka: Friedrich Miescher Institute for Biomedical Research
Georg Petzold: Friedrich Miescher Institute for Biomedical Research
Yen- Der Li: Broad Institute of MIT and Harvard
Manisha Manojkumar: Broad Institute of MIT and Harvard
Richard D. Bunker: Friedrich Miescher Institute for Biomedical Research
Katherine A. Donovan: Harvard Medical School
Quinlan L. Sievers: Broad Institute of MIT and Harvard
Jonas Koeppel: Broad Institute of MIT and Harvard
Dakota Suchyta: Friedrich Miescher Institute for Biomedical Research
Adam S. Sperling: Broad Institute of MIT and Harvard
Emma C. Fink: Broad Institute of MIT and Harvard
Jessica A. Gasser: Broad Institute of MIT and Harvard
Li R. Wang: Broad Institute of MIT and Harvard
Steven M. Corsello: Broad Institute of MIT and Harvard
Rob S. Sellar: Broad Institute of MIT and Harvard
Max Jan: Broad Institute of MIT and Harvard
Dennis Gillingham: University of Basel
Claudia Scholl: German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)
Stefan Fröhling: German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)
Todd R. Golub: Broad Institute of MIT and Harvard
Eric S. Fischer: Harvard Medical School
Nicolas H. Thomä: Friedrich Miescher Institute for Biomedical Research
Benjamin L. Ebert: Broad Institute of MIT and Harvard

Nature, 2020, vol. 585, issue 7824, 293-297

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-2374-x

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