Discovery of GSK1070916, a Potent and Selective Inhibitor of Aurora B/C Kinase

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• 作者：Nicholas D. Adams ; Jerry L. Adams ; Joelle L. Burgess ; Amita M. Chaudhari ; Robert A. Copeland ; Carla A. Donatelli ; David H. Drewry ; Kelly E. Fisher ; Toshihiro Hamajima ; Mary Ann Hardwicke ; William F. H
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：May 27, 2010
• 年：2010
• 卷：53
• 期：10
• 页码：3973-4001
• 全文大小：1535K
• 年卷期：v.53,no.10(May 27, 2010)
• ISSN：1520-4804

文摘

The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K_i* values of 0.38 ± 0.29 and 1.5 ± 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC₅₀ = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.