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Yeast as a model system to screen purine derivatives against human CDK1 and CDK2 kinases

Paper ID Volume ID Publish Year Pages File Format Full-Text
22936 43401 2015 7 PDF Available
Title
Yeast as a model system to screen purine derivatives against human CDK1 and CDK2 kinases
Abstract

•Set up a yeast-based system for screening specific human CDK inhibitors.•Proof of principle screen validates the efficiency of this system.•The screening protocol can be robotized for exploring large chemical libraries.

Cyclin-dependent kinases (Cdk) play crucial roles in cell cycle progression. Aberrant activation of Cdk1 has been observed in a number of primary tumors and Cdk2 is deregulated in various malignancies. The therapeutic value of targeting Cdk1 and Cdk2 has been explored in a number of experimental systems. In the present study, taking advantage of the fact that deletion of the yeast CDC28 gene is functionally complemented by human CDK1 or CDK2, we set up an in vivo screen system to evaluate the inhibitory potency of purine derivatives against these two human Cdks. We constructed three isogenic strains highly sensitive to small molecules and harboring genes CDK1, CDK2 or CDC28, under the control of the CDC28 promoter. In a proof of principle assay, we determined the inhibitory effect of 82 purine derivatives on the growth rate of these strains. Thirty-three of them were revealed to be able to inhibit the Cdk1- or Cdk2-harboring strains but not the Cdc28-harboring strain, suggesting a specific inhibitory effect on human Cdks. Our data demonstrate that the yeast-based assay is an efficient system to identify potential specific inhibitors that should be preferentially selected for further investigation in cultured human cell lines.

Keywords
CDK, cyclin-dependent kinase; cDNA, complementary DNA; DMSO, dimethylsulfoxide; ABC transporter, ATP-binding cassette transporters; GI50, 50% growth inhibition; IC50, half maximal inhibitory concentrationCyclin-dependent kinases; Purine derivatives; Yeast
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Yeast as a model system to screen purine derivatives against human CDK1 and CDK2 kinases
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Publisher
Database: Elsevier - ScienceDirect
Journal: Journal of Biotechnology - Volume 195, 10 February 2015, Pages 30–36
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us