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Aminopyrazine Inhibitors Binding to an Unusual Inactive Conformation of the Mitotic Kinase Nek2: SAR and Structural Characterization

Whelligan, DK, Solanki, S, Taylor, D, Thomson, DW, Cheung, KMJ, Boxall, K, Mas-Droux, C, Barillari, C, Burns, S, Grummitt, CG, Collins, I, van Montfort, RLM, Aherne, GW, Bayliss, R and Hoelder, S (2010) Aminopyrazine Inhibitors Binding to an Unusual Inactive Conformation of the Mitotic Kinase Nek2: SAR and Structural Characterization J Med Chem, 53 (21). pp. 7682-7698.

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Abstract

We report herein the first systematic exploration of inhibitors of the mitotic kinase Nek2. Starting from HTS hit aminopyrazine 2, compounds with improved activity were identified using structure-based design. Our structural biology investigations reveal two notable observations. First, 2 and related compounds bind to an unusual, inactive conformation of the kinase which to the best of our knowledge has not been reported for other types of kinase inhibitors. Second, a phenylalanine residue at the center of the ATP pocket strongly affects the ability of the inhibitor to bind to the protein. The implications of these observations are discussed, and the work described here defines key features for potent and selective Nek2 inhibition, which will aid the identification of more advanced inhibitors of Nek2.

Item Type: Article
Divisions : Faculty of Engineering and Physical Sciences > Chemistry
Authors :
AuthorsEmailORCID
Whelligan, DKUNSPECIFIEDUNSPECIFIED
Solanki, SUNSPECIFIEDUNSPECIFIED
Taylor, DUNSPECIFIEDUNSPECIFIED
Thomson, DWUNSPECIFIEDUNSPECIFIED
Cheung, KMJUNSPECIFIEDUNSPECIFIED
Boxall, KUNSPECIFIEDUNSPECIFIED
Mas-Droux, CUNSPECIFIEDUNSPECIFIED
Barillari, CUNSPECIFIEDUNSPECIFIED
Burns, SUNSPECIFIEDUNSPECIFIED
Grummitt, CGUNSPECIFIEDUNSPECIFIED
Collins, IUNSPECIFIEDUNSPECIFIED
van Montfort, RLMUNSPECIFIEDUNSPECIFIED
Aherne, GWUNSPECIFIEDUNSPECIFIED
Bayliss, RUNSPECIFIEDUNSPECIFIED
Hoelder, SUNSPECIFIEDUNSPECIFIED
Date : 11 November 2010
Identification Number : 10.1021/jm1008727
Uncontrolled Keywords : CROSS-COUPLING REACTIONS, PROTEIN-KINASE, CENTROSOME SEPARATION, DNA-DAMAGE, NIMA, CANCER, PHOSPHORYLATION, IDENTIFICATION, SUBSTRATE, ANALOGS
Depositing User : Symplectic Elements
Date Deposited : 02 Mar 2012 15:06
Last Modified : 09 Jun 2014 13:37
URI: http://epubs.surrey.ac.uk/id/eprint/235558

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