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鈭扐ctivity Relationship

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• 作者：Savade Solanki ; Paolo Innocenti ; Corine Mas-Droux ; Kathy Boxall ; Caterina Barillari ; Rob L. M. van Montfort ; G. Wynne Aherne ; Richard Bayliss ; Swen Hoelder
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 24, 2011
• 年：2011
• 卷：54
• 期：6
• 页码：1626-1639
• 全文大小：1253K
• 年卷期：v.54,no.6(March 24, 2011)
• ISSN：1520-4804

文摘

We describe herein the structure鈭抋ctivity 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.