The cell fate-determining roles played by members of the cyclin-dependent protein kinase (CDK) family explain why their dysregulation can promote proliferative diseases, and identify them as potential targets for drug discovery in oncology and beyond. After many years of research, the first efficacious CDK inhibitors have now been registered for clinical use in a defined segment of breast cancer. Research is underway to identify inhibitors with appropriate CDK-inhibitory profiles to recapitulate this success in other disease settings. Here, we review the structural data that illustrate the interactions and properties that confer upon inhibitors affinity and/or selectivity toward different CDK family members. We conclude that where CDK inhibitors display selectivity, that selectivity derives from exploiting active site sequence peculiarities and/or from the capacity of the target CDK(s) to access conformations compatible with optimizing inhibitor–target interactions.
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November 2017
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The small molecule inhibitor of the Wnt pathway CCT251545 (gold) bound to CDK8-cyclin C (PDB 5BNJ), with the 2Fo-Fc electron density superimposed as a blue chicken-wire mesh contoured at 1σ (blue), based the research of Dale et al. [Nat. Chem. Biol. (2015) 11, 973–980]. The inhibitor can be used as a chemical tool to explore the role of the Mediator complex in human disease. Image kindly provided by Paul Workman and Rob van Montfort.Close Modal
Review Article|
November 08 2017
Structure-based discovery of cyclin-dependent protein kinase inhibitors
Mathew P. Martin;
Mathew P. Martin
1Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, U.K.
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Jane A. Endicott;
Jane A. Endicott
2Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, U.K.
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Martin E.M. Noble
3Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, U.K.
Correspondence: Martin E.M. Noble (martin.noble@ncl.ac.uk)
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Essays Biochem (2017) 61 (5): 439–452.
Article history
Received:
August 13 2017
Revision Received:
September 24 2017
Accepted:
September 25 2017
Citation
Rob L.M. van Montfort, Paul Workman, Mathew P. Martin, Jane A. Endicott, Martin E.M. Noble; Structure-based discovery of cyclin-dependent protein kinase inhibitors. Essays Biochem 8 November 2017; 61 (5): 439–452. doi: https://doi.org/10.1042/EBC20170040
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