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Qingping Zeng,
Matthew P Bourbeau,
G Erich Wohlhieter,
Guomin Yao,
Holger Monenschein, James T Rider,
Matthew R Lee,
Shiwen Zhang,
Julie Lofgren,
Daniel Freeman,
Chun Li,
Elizabeth Tominey,
Xin Huang,
Douglas Hoffman,
Harvey Yamane,
Andrew S Tasker,
Celia Dominguez,
Vellarkad N Viswanadhan,
Randall Hungate,
Xiaoling Zhang
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ABSTRACT: A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.
Bioorganic & medicinal chemistry letters 01/2010; 20(5):1652-6. · 2.65 Impact Factor
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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, [......],
Suijin Yang,
Chun Li,
Elizabeth Tominey,
Xin Huang,
Douglas Hoffman,
Harvey K Yamane,
Christopher Fotsch,
Celia Dominguez,
Randall Hungate,
Xiaoling Zhang
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ABSTRACT: Through a combination of screening and structure-based rational design, we have discovered a series of N(1)-(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.
Bioorganic & medicinal chemistry letters 01/2010; 20(5):1559-64. · 2.65 Impact Factor
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ABSTRACT: [reaction: see text] A series of 4-alkyl-5-aminoisoxazoles have been synthesized in high yield by nucleophilic addition of lithiated alkyl nitriles to (alpha)-chlorooximes. The scope and limitations of this reaction were examined by varying the nature of the nitrile and chloride oxime.
Organic Letters 09/2006; 8(17):3679-80. · 5.86 Impact Factor
