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

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 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.

• Authors: 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 Bouska, Alexander Shoemaker, Anatol Oleksijew, Ken Jarvis, Chang Park, Ron De Jong, Tilman Oltersdorf, Qun Li, Saul H Rosenberg, Vincent L Giranda
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 16 Issue 13 Pg. 3424-9 (Jul 01 2006) ISSN: 0960-894X [Print] England
• PMID: 16644221 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Indoles
• Oxindoles
• Protein Kinase Inhibitors
• Pyridines
• 2-oxindole
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Crystallography, X-Ray
• Dose-Response Relationship, Drug
• Indoles (chemistry)
• Mice
• Models, Molecular
• Molecular Structure
• Neoplasms (drug therapy)
• Oxindoles
• Protein Kinase Inhibitors (administration & dosage, chemistry, pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Pyridines (chemistry)
• Stereoisomerism
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays