Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Highlight
  • Published:

Structure-based drug design

Cycle stopper

Nature Reviews Drug Discovery volume 1, pages 96–97 (2002)Cite this article

Taking the crystal structure of activated CDK2 as a basis for a model of CDK4, a new de novo design strategy was used to identify promising drug scaffolds. Commonly, the structures that are obtained from de novo design progams are difficult to synthesize and their components are not readily available. So, to counteract any such potential problems, the authors constructed a program to extract essential parts of the structures and check their availability and/or synthetic accessibility. Scaffold candidates were then screened in a CDK4 inhibition assay, and one hit was chosen as the basis for library synthesis. Structure–activity relationship studies and further molecular modelling allowed the binding mode of this series of lead compounds to be deduced, and a compound that potently inhibited CDK4 was identified.

But what about the selectivity? Although the identified compound was moderately (>50-fold) selective over kinases not in the CDK family, it had comparable activity against CDK1 and CDK2. To address this problem, the authors used molecular modelling to identify the amino acids that were most specific for the active site of CDK4, and then used de novo design based on the deduced binding mode to generate a library of compounds tailored to interact with these residues. As a result, a compound that was both a potent inhibitor of CDK4 and selective over other CDKs (>190-fold) and other kinases (>530-fold) was identified, and was found to cause cell-cycle arrest of a cancer cell line in the G1 phase.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

ORIGINAL RESEARCH PAPERS

  1. Honma, T. et al. Structure-based generation of a new class of potent Cdk4 inhibitors: new de novo design strategy and library design. J. Med. Chem. 44, 4615–4627 (2001)

    Article  CAS  Google Scholar 

  2. Honma, T. et al. A novel approach for the development of selective Cdk4 inhibitors: library design based on locations of Cdk4 specific amino acid residues. J. Med. Chem. 44, 4628–4640 (2001)

    Article  CAS  Google Scholar 

FURTHER READING

  1. Ikuta, M. et al. Crystallographic approach to identification of cyclin-dependent kinase 4 (CDK4)-specific inhibitors by using CDK4 mimic CDK2 protein. J. Biol. Chem. 276, 27548–27554 (2001)

    Article  CAS  Google Scholar 

Download references

Authors
  1. Peter Kirkpatrick
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kirkpatrick, P. Cycle stopper. Nat Rev Drug Discov 1, 96–97 (2002). https://doi.org/10.1038/nrd734

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd734

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing