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

Bioorganic & Medicinal Chemistry Letters
Gui-Dong ZhuVincent L Giranda

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.

References

Jun 24, 2004·Expert Opinion on Investigational Drugs·Joell J Gills, Phillip A Dennis
Jun 16, 2005·Molecular Cancer Therapeutics·Yan LuoVincent L Giranda
Apr 11, 2006·Bioorganic & Medicinal Chemistry Letters·Gui-Dong ZhuVincent L Giranda

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Citations

Oct 1, 2011·Journal of Chemical Information and Modeling·Yan LiZigang Dong
Feb 16, 2010·Journal of Molecular Graphics & Modelling·Subhash AjmaniSudhir A Kulkarni
May 9, 2015·Seminars in Cancer Biology·Abbas K SamadiXujuan Yang
Jun 4, 2011·Expert Opinion on Therapeutic Patents·Margrith E MattmannCraig W Lindsley
Mar 16, 2017·The Journal of Organic Chemistry·Ling-Chao YuXingang Zhang
Jan 30, 2009·Basic & Clinical Pharmacology & Toxicology·Rogelio Paniagua-PérezJavier Pérez-Gallaga
Jul 7, 2010·Electrophoresis·Dechen JiangNancy L Allbritton
Jun 9, 2016·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Michail N ElinsonFedor V Ryzhkov
May 15, 2007·Journal of Combinatorial Chemistry·Jinwen XieYongping Yu

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