Azole-based inhibitors of AKT/PKB for the treatment of cancer

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• 作者：Qingping Zeng ; John G. Allen ; Matthew P. Bourbeau ; Xianghong Wang ; Guomin Yao ; Seifu Tadesse ; James T. Rider ; Chester C. Yuan ; Fang-Tsao Hong ; Matthew R. Lee ; Shiwen Zhang ; Julie A. Lofgren ; Daniel J.
• 关键词：PKB ; AKT ; Cancer ; SAR studies
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2010
• 出版时间：1 March 2010
• 年：2010
• 卷：20
• 期：5
• 页码：1559-1564
• 全文大小：449 K

文摘

Through a combination of screening and structure-based rational design, we have discovered a series of Np>1p>-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.