Quantifying CDK inhibitor selectivity in live cells

Carrow I. Wells, James D. Vasta, Cesear R. Corona, Jennifer Wilkinson, Chad A. Zimprich, Morgan R. Ingold, Julie E. Pickett, David H. Drewry, Kathryn M. Pugh, Marie K. Schwinn, Byounghoon (Brian) Hwang, Hicham Zegzouti, Kilian V. M. Huber, Mei Cong, Poncho L. Meisenheimer, Timothy M. Willson () and Matthew B. Robers ()
Additional contact information
Carrow I. Wells: University of North Carolina at Chapel Hill
James D. Vasta: Promega Corporation
Cesear R. Corona: Promega Corporation
Jennifer Wilkinson: Promega Corporation
Chad A. Zimprich: Promega Corporation
Morgan R. Ingold: Promega Corporation
Julie E. Pickett: University of North Carolina at Chapel Hill
David H. Drewry: University of North Carolina at Chapel Hill
Kathryn M. Pugh: University of Oxford
Marie K. Schwinn: Promega Corporation
Byounghoon (Brian) Hwang: Promega Corporation
Hicham Zegzouti: Promega Corporation
Kilian V. M. Huber: University of Oxford
Mei Cong: Promega Corporation
Poncho L. Meisenheimer: Promega Corporation
Timothy M. Willson: University of North Carolina at Chapel Hill
Matthew B. Robers: Promega Corporation

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-16559-0

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