Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 16, Issue 13, Pages 3424-3429Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2006.04.005
Keywords
Akt inhibitor; protein kinase B; PKB; GSK3; FL5.12-Akt; anticancer
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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 (Ilk) less selective. In a mouse xenograft model, 9d, 11f, and 11n inhibited tumor growth but with accompanying toxicity. (c) 2006 Elsevier Ltd. All rights reserved.
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