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Discovery and SAR of oxindole–pyridine-based protein kinase B/Akt inhibitors for treating cancers

2006; Elsevier BV; Volume: 16; Issue: 13 Linguagem: Inglês

10.1016/j.bmcl.2006.04.005

1464-3405

Gui‐Dong Zhu, Viraj B. Gandhi, Jianchun Gong, Yan Luo, Xuesong Liu, Yan Shi, Ran Guan, Shayna R. Magnone, Vered Klinghofer, Eric F. Johnson, Jennifer J. Bouska, Alexander R. Shoemaker, Anatol Oleksijew, Ken Jarvis, Chang Park, Ron de Jong, Tilman Oltersdorf, Qun Li, Saul H. Rosenberg, Vincent L. Giranda,

Biochemical and Molecular Research

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.