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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Quantifying CDK inhibitor selectivity in live cells

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Wells, Carrow I. [1] ; Vasta, James D. [2] ; Corona, Cesear R. [2] ; Wilkinson, Jennifer [2] ; Zimprich, Chad A. [2] ; Ingold, Morgan R. [2] ; Pickett, Julie E. [1] ; Drewry, David H. [1] ; Pugh, Kathryn M. [3, 4] ; Schwinn, Marie K. [2] ; Hwang, Byounghoon (Brian) [2] ; Zegzouti, Hicham [2] ; Huber, Kilian V. M. [3, 4] ; Cong, Mei [2] ; Meisenheimer, Poncho L. [2] ; Willson, Timothy M. [1] ; Robers, Matthew B. [2]
Total Authors: 17
[1] Univ N Carolina, UNC Eshelman Sch Pharm, Struct Genom Consortium, Chapel Hill, NC 27599 - USA
[2] Promega Corp, 2800 Woods Hollow Rd, Madison, WI 53711 - USA
[3] Univ Oxford, Nuffield Dept Med, Target Discovery Inst, Oxford - England
[4] Univ Oxford, Nuffield Dept Med, Struct Genom Consortium, Oxford - England
Total Affiliations: 4
Document type: Journal article
Source: NATURE COMMUNICATIONS; v. 11, n. 1 JUN 2 2020.
Web of Science Citations: 0

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. Cyclin-dependent kinase (CDK) inhibitors are widely used both in the clinic and for basic research aimed at dissecting the specific cellular functions of specific CDKs. Here, the authors report the development of a panel of fluorescent reporter probes and provide a comprehensive profile of the inhibitory activity of several CDK inhibitors towards all 21 CDKs in living cells. (AU)

FAPESP's process: 14/50897-0 - INCT 2014: Open-acess Medicinal Chemistry Centre (OpenMedChem)
Grantee:Katlin Brauer Massirer
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research
Grantee:Paulo Arruda
Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE
FAPESP's process: 16/17469-0 - Development of celular assays to measure and to discover the phenotypic consequences of chemical inhibition of Vaccinia-Related Kinase 1 (VRK1)
Grantee:Roberta Regina Ruela de Sousa
Support Opportunities: Scholarships in Brazil - Post-Doctoral