Research Papers:

Structure-guided design of purine-based probes for selective Nek2 inhibition

Christopher R. Coxon, Christopher Wong, Richard Bayliss, Kathy Boxall, Katherine H. Carr, Andrew M. Fry, Ian R. Hardcastle, Christopher J. Matheson, David R. Newell, Mangaleswaran Sivaprakasam, Huw Thomas, David Turner, Sharon Yeoh, Lan Z. Wang, Roger J. Griffin, Bernard T. Golding and Céline Cano _

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Oncotarget. 2017; 8:19089-19124. https://doi.org/10.18632/oncotarget.13249

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Christopher R. Coxon1, Christopher Wong1, Richard Bayliss2, Kathy Boxall3, Katherine H. Carr2, Andrew M. Fry2, Ian R. Hardcastle1, Christopher J. Matheson1, David R. Newell4, Mangaleswaran Sivaprakasam1, Huw Thomas4, David Turner1, Sharon Yeoh2, Lan Z. Wang4, Roger J. Griffin1,*, Bernard T. Golding1, Céline Cano1

1Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, UK

2Department of Molecular and Cell Biology, University of Leicester, Leicester, UK

3Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK

4Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK

*Deceased 24 September 2014

Correspondence to:

Céline Cano, email: [email protected]

Keywords: cancer, Nek2, small molecule inhibitors, structure-guided design

Received: July 13, 2016     Accepted: October 17, 2016     Published: November 09, 2016


Nek2 (NIMA-related kinase 2) is a cell cycle-dependent serine/threonine protein kinase that regulates centrosome separation at the onset of mitosis. Overexpression of Nek2 is common in human cancers and suppression can restrict tumor cell growth and promote apoptosis. Nek2 inhibition with small molecules, therefore, offers the prospect of a new therapy for cancer. To achieve this goal, a better understanding of the requirements for selective-inhibition of Nek2 is required. 6-Alkoxypurines were identified as ATP-competitive inhibitors of Nek2 and CDK2. Comparison with CDK2-inhibitor structures indicated that judicious modification of the 6-alkoxy and 2-arylamino substituents could achieve discrimination between Nek2 and CDK2. In this study, a library of 6-cyclohexylmethoxy-2-arylaminopurines bearing carboxamide, sulfonamide and urea substituents on the 2-arylamino ring was synthesized. Few of these compounds were selective for Nek2 over CDK2, with the best result being obtained for 3-((6-(cyclohexylmethoxy)-9H-purin-2-yl)amino)-N,N-dimethylbenzamide (CDK2 IC50 = 7.0 μM; Nek2 IC50 = 0.62 μM) with >10-fold selectivity. Deletion of the 6-substituent abrogated activity against both Nek2 and CDK2. Nine compounds containing an (E)-dialkylaminovinyl substituent at C-6, all showed selectivity for Nek2, e.g. (E)-6-(2-(azepan-1-yl)vinyl)-N-phenyl-9H-purin-2-amine (CDK2 IC50 = 2.70 μM; Nek2 IC50 = 0.27 μM). Structural biology of selected compounds enabled a partial rationalization of the observed structure activity relationships and mechanism of Nek2 activation. This showed that carboxamide 11 is the first reported inhibitor of Nek2 in the DFG-in conformation.

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