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Concerted multidisciplinary efforts have led to the development of Cyclin-Dependent Kinase inhibitors (CDKi's) as small molecule drugs and chemical probes of intracellular CDK function. However, conflicting data has been reported on the inhibitory potency of CDKi's and a systematic characterization of affinity and selectivity against intracellular CDKs is lacking. We have developed a panel of cell-permeable energy transfer probes to quantify target occupancy for all 21 human CDKs in live cells, and present a comprehensive evaluation of intracellular isozyme potency and selectivity for a collection of 46 clinically-advanced CDKi's and tool molecules. We observed unexpected intracellular activity profiles for a number of CDKi's, offering avenues for repurposing of highly potent molecules as probes for previously unreported targets. Overall, we provide a broadly applicable method for evaluating the selectivity of CDK inhibitors in living cells, and present a refined set of tool molecules to study CDK function.

Original publication

DOI

10.1038/s41467-020-16559-0

Type

Journal article

Journal

Nat Commun

Publication Date

02/06/2020

Volume

11

Keywords

CDC2 Protein Kinase, Cell Cycle Checkpoints, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Cyclin-Dependent Kinase 9, Cyclin-Dependent Kinase Inhibitor Proteins, Cyclin-Dependent Kinases, Enzyme Inhibitors, HEK293 Cells, Humans, Phosphorylation, Structure-Activity Relationship