Author/Authors :
Gui-Dong Zhu، نويسنده , , Viraj B. Gandhi، نويسنده , , Jianchun Gong، نويسنده , , Yan Luo، نويسنده , , Xuesong Liu، نويسنده , , Yan Shi، نويسنده , , Ran Guan، نويسنده , , Shayna R. Magnone، نويسنده , , Vered Klinghofer، نويسنده , , Eric F. Johnson، نويسنده , , Jennifer Bouska، نويسنده , , Alexander Shoemaker، نويسنده , , Anatol Oleksijew، نويسنده , , Ken Jarvis، نويسنده , , Chang Park، نويسنده , , Ron De Jong، نويسنده , , Tilman Oltersdorf، نويسنده , , Qun Li، نويسنده , , Saul H. Rosenberg، نويسنده , , Vincent L. Giranda، نويسنده ,
Abstract :
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 IC50 of 0.17 nM 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.
