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

DOI: 10.18632/oncotarget.13249 DOI Help

Authors: Christopher R. Coxon (Newcastle University) , Christopher Wong (Newcastle University) , Richard Bayliss (University of Leicester) , Kathy Boxall (The Institute of Cancer Research) , Katherine H. Carr (University of Leicester) , Andrew M. Fry (University of Leicester) , Ian R. Hardcastle (Newcastle University) , Christopher J. Matheson (Newcastle University) , David R. Newell (Newcastle University) , Mangaleswaran Sivaprakasam (Newcastle University) , Huw Thomas (Newcastle University) , David Turner (Newcastle University) , Sharon Yeoh (University of Leicester) , Lan Z. Wang (Newcastle University) , Roger J. Griffin (Newcastle University) , Bernard T. Golding (Newcastle University) , Céline Cano (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Oncotarget

State: Published (Approved)
Published: November 2016
Diamond Proposal Number(s): 307 , 6385

Open Access Open Access

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.

Journal Keywords: cancer; Nek2; small molecule inhibitors; structure-guided design

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 20/04/2017 11:48


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)