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Quantifying CDK inhibitor selectivity in live cells

Author

Listed:
  • 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
    University of Oxford)

  • Marie K. Schwinn

    (Promega Corporation)

  • Byounghoon (Brian) Hwang

    (Promega Corporation)

  • Hicham Zegzouti

    (Promega Corporation)

  • Kilian V. M. Huber

    (University of Oxford
    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)

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.

Suggested Citation

  • 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 (B, 2020. "Quantifying CDK inhibitor selectivity in live cells," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16559-0
    DOI: 10.1038/s41467-020-16559-0
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