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Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor

Nature Structural Biology volume 9, pages 745–749 (2002)Cite this article

Abstract

Aberrant control of cyclin-dependent kinases (CDKs) is a central feature of the molecular pathology of cancer. Iterative structure-based design was used to optimize the ATP- competitive inhibition of CDK1 and CDK2 by O6-cyclohexylmethylguanines, resulting in O6-cyclohexylmethyl-2-(4′- sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than the parent compound (Ki values for CDK1 = 9 nM and CDK2 = 6 nM versus 5,000 nM and 12,000 nM, respectively, for O6-cyclohexylmethylguanine). The increased potency arises primarily from the formation of two additional hydrogen bonds between the inhibitor and Asp 86 of CDK2, which facilitate optimum hydrophobic packing of the anilino group with the specificity surface of CDK2. Cellular studies with O6-cyclohexylmethyl-2-(4′- sulfamoylanilino) purine demonstrated inhibition of MCF-7 cell growth and target protein phosphorylation, consistent with CDK1 and CDK2 inhibition. The work represents the first successful iterative synthesis of a potent CDK inhibitor based on the structure of fully activated CDK2–cyclin A. Furthermore, the potency of O6-cyclohexylmethyl-2-(4′- sulfamoylanilino)purine was both predicted and fully rationalized on the basis of protein–ligand interactions.

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Figure 1: Inhibitor structures and binding of NU2058 to T160pCDK2–cyclinA.
Figure 2: Binding of NU6094, NU6086 and NU6102 to T160pCDK2–cyclinA.
Figure 3: Inhibition of CDK2- and CDK1-specific phosphorylation events by NU2058 and NU6102.

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Acknowledgements

We would like to thank T. Hunt for his gift of the human CDK2 and cyclin A3 cDNAs and C. Man for the Saccharomyces cerevisiae CIV1 sequence. We thank N. Hanlon, N. Brown and D. Barford for the development of the CDK2-CIV1 co-expression strategy. We also thank the beamline staff at ESRF, Grenoble, France, who provided excellent facilities and advice during data collection. We wish to acknowledge the use of the EPSRC's Database Service at Daresbury. At the LMB, the authors would like to thank I. Taylor, E. Garman, A. Lawrie, R. Bryan, Y. Huang, K. Measures and S. Lee, and L. Meijer at CNRS Station Biologique, Roscoff, for advice on the nucleolin western blotting procedure. This research was supported by grants from Cancer Research UK, The Royal Society UK, Medical Research Council UK, BBSRC and AstraZeneca PLC UK.

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Author notes

  1. Hayley J. Whitfield: This work is dedicated to the memory of Hayley J. Whitfield.

Authors and Affiliations

  1. Laboratory of Molecular Biophysics and Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK

    Thomas G. Davies, Jane A. Endicott, Louise N. Johnson, Martin E.M. Noble & Julie A. Tucker

  2. Cancer Research Unit and Department of Chemistry, University of Newcastle, Newcastle upon Tyne, NE2 4HH, UK

    Johanne Bentley, Christine E. Arris, Nicola J. Curtin, Ashleigh E. Gibson, Bernard T. Golding, Roger J. Griffin, Ian R. Hardcastle, Veronique Mesguiche, David R. Newell, Lan Wang & Hayley J. Whitfield

  3. AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, SK10 4TG, UK

    F. Thomas Boyle & Philip Jewsbury

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Correspondence to David R. Newell.

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Davies, T., Bentley, J., Arris, C. et al. Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor. Nat Struct Mol Biol 9, 745–749 (2002). https://doi.org/10.1038/nsb842

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