Discovery and Optimization of a Series of 3-(3-Phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: Orally Bioavailable, Selective, and Potent ATP-Independent Akt Inhibitors
Discovery and Optimization of a Series of 3-(3-Phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: Orally Bioavailable, Selective, and Potent ATP-Independent Akt Inhibitors
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DOI：
10.1021/jm300276x
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发表时间：
2012-06-14
影响因子：
7.3
通讯作者：
Chan, Thomas C. K.
中科院分区：
文献类型：
--
作者：
Ashwell, Mark A.;Lapierre, Jean-Marc;Chan, Thomas C. K.
本文介绍了一种生物化学和生物物理学筛选策略的实施，以确定和优化小分子Akt1抑制剂，其作用机制与激酶结构域ATP竞争性抑制剂不同。借助于在2.25 A下溶解的12 j的未磷酸化的Akt1共晶体结构，可以证实，作为结合这些新抑制剂的结果，ATP结合裂缝含有许多疏水残基，其如预期地封闭ATP结合。这些Akt抑制剂在体外有效抑制细胞内Akt活化及其下游靶标（PRAS 40）。用两个实施例12 e和12 j进行的体内药效学和药代动力学研究显示，在小鼠中口服给药后，该系列在抑制Akt和另外的下游效应物（p70 S6）的活化方面类似地有效。
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 A, 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 and additional downstream effector (p70S6) following oral dosing in mice.