Li Qun, Woods Keith W, Thomas Sheela, Zhu Gui-Dong, Packard Garrick, Fisher John, Li Tongmei, Gong Jianchun, Dinges Jurgen, Song Xiaohong, Abrams Jason, Luo Yan, Johnson Eric F, Shi Yan, Liu Xuesong, Klinghofer Vered, Des Jong Ron, Oltersdorf Tilman, Stoll Vincent S, Jakob Clarissa G, Rosenberg Saul H, Giranda Vincent L
Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6101, USA.
Bioorg Med Chem Lett. 2006 Apr 1;16(7):2000-7. doi: 10.1016/j.bmcl.2005.12.065. Epub 2006 Jan 18.
Structure-based design and synthesis of the 3,4'-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor with an IC(50) of 1.3nM against Akt1. Compound 13a shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to marginal selectivity against closely related kinases in the AGC and CMGC families. Moreover, 13a demonstrates potent cellular activity comparable to staurosporine, with IC(50) values of 0.42 and 0.59microM against MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of phosphorylation of the Akt downstream target GSK3 was also observed in FL5.12-Akt1 cells with an EC(50) of 1.5microM. The X-ray structures of 12 and 13a in complex with PKA in the ATP-binding site were determined.
基于结构的3,4'-双吡啶乙烯系列的设计与合成，促使3-异喹啉基吡啶13a被发现，它是一种有效的蛋白激酶B/蛋白激酶B（PKB/Akt）抑制剂，对Akt1的半数抑制浓度（IC(50)）为1.3纳摩尔。化合物13a对不同激酶家族（如酪氨酸激酶和钙/钙调蛋白依赖性蛋白激酶（CAMK））表现出优异的选择性，而对AGC和CMGC家族中密切相关的激酶，其选择性较差或仅为边缘选择性。此外，13a显示出与星形孢菌素相当的强大细胞活性，对MiaPaCa-2细胞和过表达Akt1的FL5.12-Akt1细胞的IC(50)值分别为0.42和0.59微摩尔。在FL5.12-Akt1细胞中也观察到对Akt下游靶点糖原合成酶激酶3（GSK3）磷酸化的抑制，其半数效应浓度（EC(50)）为1.5微摩尔。确定了12和13a与蛋白激酶A（PKA）在ATP结合位点形成复合物的X射线晶体结构。
