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I03-Macromolecular Crystallography I04-Macromolecular Crystallography	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 , Céline Cano Oncotarget DOI: 10.18632/oncotarget.13249 Diamond Proposal Number(s): [307, 6385] Open Access Show Abstract ▼ Abstract: 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.	Nov 2016

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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography

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