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Title: Benzimidazole inhibitors induce a DFG-out conformation of never in mitosis gene A-related kinase 2 (Nek2) without binding to the back pocket and reveal a nonlinear structure-activity relationship.
Authors: Solanki, S
Innocenti, P
Mas-Droux, C
Boxall, K
Barillari, C
van Montfort RL
Aherne, GW
Bayliss, R
Hoelder, S
First Published: 24-Mar-2011
Citation: J MED CHEM, 2011, 54 (6), pp. 1626-1639
Abstract: We describe herein the structure-activity relationship (SAR) and cocrystal structures of a series of Nek2 inhibitors derived from the published polo-like kinase 1 (Plk1) inhibitor (R)-1. Our studies reveal a nonlinear SAR for Nek2 and our cocrystal structures show that compounds in this series bind to a DFG-out conformation of Nek2 without extending into the enlarged back pocket commonly found in this conformation. These observations were further investigated, and structure-based design led to Nek2 inhibitors derived from (R)-1 with more than a hundred-fold selectivity against Plk1.
DOI Link: 10.1021/jm1011726
eISSN: 1520-4804
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Biochemistry

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