AKT1 的 2-氨基噻二唑抑制剂作为潜在的癌症治疗药物。
2-Aminothiadiazole inhibitors of AKT1 as potential cancer therapeutics.
机构信息
Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
出版信息
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1652-6. doi: 10.1016/j.bmcl.2010.01.046. Epub 2010 Jan 20.
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.
描述了一系列作为 AKT1 抑制剂的 2-氨基噻二唑类化合物。讨论了 SAR 关系，以及对蛋白激酶 A（PKA）和细胞周期蛋白依赖性激酶 2（CDK2）的选择性。通过 X 射线晶体学分析，合理地解释了几种化合物对 AKT1 与 PKA 的中度选择性。关键化合物在细胞测定中表现出对两种 AKT 底物 PRAS40 和 FKHRL1 的磷酸化的活性。化合物 30 被推进到小鼠肝 PD 测定中，在该测定中，它显示出 AKT 活性的剂量依赖性抑制，如通过抑制磷酸化 PRAS40 来测量。
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