Zhu Gui-Dong, Gandhi Viraj B, Gong Jianchun, Luo Yan, Liu Xuesong, Shi Yan, Guan Ran, Magnone Shayna R, Klinghofer Vered, Johnson Eric F, Bouska Jennifer, Shoemaker Alexander, Oleksijew Anatol, Jarvis Ken, Park Chang, Jong Ron De, Oltersdorf Tilman, Li Qun, Rosenberg Saul H, Giranda Vincent L
Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA.
Bioorg Med Chem Lett. 2006 Jul 1;16(13):3424-9. doi: 10.1016/j.bmcl.2006.04.005. Epub 2006 Apr 27.
We describe a series of potent and selective oxindole-pyridine-based protein kinase B/Akt inhibitors. The most potent compound 11n in this series demonstrated an IC(50) of 0.17nM against Akt1 and more than 100-fold selectivity over other Akt isozymes. The selectivity against other protein kinases was highly dependent on the C-3 substitutions at the oxindole scaffold, with unsubstituted 9e or 3-furan-2-ylmethylene (11n) more selective and 3-(1H-pyrrol-2-yl)methylene (11f) or 3-(1H-imidazol-2-yl)methylene (11k) less selective. In a mouse xenograft model, 9d, 11f, and 11n inhibited tumor growth but with accompanying toxicity.
我们描述了一系列基于氧化吲哚 - 吡啶的强效且选择性的蛋白激酶B/Akt抑制剂。该系列中最有效的化合物11n对Akt1的IC(50)为0.17nM，对其他Akt同工酶的选择性超过100倍。对其他蛋白激酶的选择性高度依赖于氧化吲哚骨架上的C-3取代基，未取代的9e或3-呋喃-2-基亚甲基（11n）选择性更高，而3-(1H-吡咯-2-基)亚甲基（11f）或3-(1H-咪唑-2-基)亚甲基（11k）选择性较低。在小鼠异种移植模型中，9d、11f和11n抑制肿瘤生长，但伴有毒性。
