Journal Article

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

Sperling, Adam S., Corsello, Steven M., Li, Yen-Der, Sievers, Quinlan L., Gasser, Jessica A., Słabicki, Mikołaj, Fischer, Eric S., Donovan, Katherine A., Thomä, Nicolas H., Petzold, Georg, Golub, Todd R., Ebert, Benjamin L., Sellar, Rob S., Bunker, Richard D., Fröhling, Stefan, Fink, Emma C., Scholl, Claudia, Wang, Li R., Gillingham, Dennis, Suchyta, Dakota, Kozicka, Zuzanna, Manojkumar, Manisha, Koeppel, Jonas, Jan, Max

2020

Overview

Molecular glue compounds induce protein–protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation 1 . Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets 2 . 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 3 – 5 , we identify CR8—a cyclin-dependent kinase (CDK) inhibitor 6 —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. The cyclin-dependent kinase inhibitor CR8 acts as a molecular glue compound by inducing the formation of a complex between CDK12–cyclin K and DDB1, which results in the ubiquitination and degradation of cyclin K.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 38 / 38/1 / 631/154/555 / 631/535/1266 / 631/92/609 / 82/58 / 82/80 / 82/83 / 96/106 / 96/109 / 96/31 / 96/33 / 96/98 / Adhesives / Analysis / Biodegradation / Cell Line, Tumor / Control / CRISPR / Cyclin-dependent kinase / Cyclin-dependent kinases / Cyclin-Dependent Kinases - antagonists & inhibitors / Cyclin-Dependent Kinases - chemistry / Cyclin-Dependent Kinases - metabolism / Cyclins / Cyclins - chemistry / Cyclins - deficiency / Cyclins - metabolism / Cytotoxicity / Degradation / Depletion / DNA-Binding Proteins - metabolism / Drugs / Enzyme inhibitors / Enzymes / Genomes / Glue / Glues / Humanities and Social Sciences / Humans / Kinases / Models, Molecular / Molecules / multidisciplinary / Proteasome Endopeptidase Complex - metabolism / Protein Binding - drug effects / Protein interaction / Proteins / Proteolysis / Proteolysis - drug effects / Purines - chemistry / Purines - pharmacology / Purines - toxicity / Pyridines - chemistry / Pyridines - pharmacology / Pyridines - toxicity / Science / Science (multidisciplinary) / Small Molecule Libraries - analysis / Small Molecule Libraries - chemistry / Small Molecule Libraries - pharmacology / Substrates / Toxicity / Ubiquitin / Ubiquitin-protein ligase / Ubiquitination / Ubiquitination - drug effects