This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP-competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 Å, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice.

中文翻译：

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发现和优化一系列的3-（3-Phenyl-3 H-咪唑并[4,5 - b ]吡啶-2-基）吡啶-2-胺：口服生物利用性，选择性和有效的非ATP依赖的Akt抑制剂

本文介绍了生化和生物物理筛选策略的实施，以识别和优化小分子Akt1抑制剂，该抑制剂通过不同于激酶域ATP竞争性抑制剂的机制起作用。借助于在2.25Å下解析的12j的未磷酸化Akt1共晶体结构，可以确认由于结合了这些新型抑制剂，ATP结合裂隙包含了许多疏水残基，这些残基如预期的那样与ATP结合。这些Akt抑制剂在体外可有效抑制细胞内Akt激活及其下游靶标（PRAS40）。带有两个示例12e和12j的体内药效学和药代动力学研究证实了该系列在小鼠口服给药后在抑制Akt和其他下游效应子（p70S6）方面同样有效。