Synthesis and structure–activity relationship of 3,4′-bispyridinylethylenes: Discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of ca

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• 作者：Qun Li ; Keith W. Woods ; Sheela Thomas ; Gui-Dong Zhu ; Garrick Packard ; John Fisher ; Tongmei Li ; Jianchun Gong ; Jurgen Dinges ; Xiaohong Song et al.
• 关键词：Inhibitors of Akt ; Akt1 ; Akt2 ; Akt3 ; PKA ; PKB ; protein kinase B ; GSK3 ; FL5.12-Akt1 ; X-ray ; Anticancer ; Apoptosis ; Antitumor ; Pharmacokinetics ; Kinase inhibitors ; Structure-based design
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2006
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 April 2006
• 卷：16
• 期：7
• 页码：2000-2007
• 文件大小：462 K

摘要

Structure-based design and synthesis of the 3,4′-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine trong>13atrong> as a potent PKB/Akt inhibitor with an IC₅₀ of 1.3 nM against Akt1. Compound trong>13atrong> shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to marginal selectivity against closely related kinases in the AGC and CMGC families. Moreover, trong>13atrong> demonstrates potent cellular activity comparable to staurosporine, with IC₅₀ values of 0.42 and 0.59 μM against MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of phosphorylation of the Akt downstream target GSK3 was also observed in FL5.12-Akt1 cells with an EC₅₀ of 1.5 μM. The X-ray structures of trong>12trong> and trong>13atrong> in complex with PKA in the ATP-binding site were determined.