Synthesis and structure-activity relationship of 3,4'-bispyridinylethylenes: discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer |
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Authors: | Li Qun Woods Keith W Thomas Sheela Zhu Gui-Dong Packard Garrick Fisher John Li Tongmei Gong Jianchun Dinges Jurgen Song Xiaohong Abrams Jason Luo Yan Johnson Eric F Shi Yan Liu Xuesong Klinghofer Vered Des Jong Ron Oltersdorf Tilman Stoll Vincent S Jakob Clarissa G Rosenberg Saul H Giranda Vincent L |
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Institution: | Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. qun.li@abbott.com |
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Abstract: | Structure-based design and synthesis of the 3,4'-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor with an IC(50) of 1.3nM against Akt1. Compound 13a shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to marginal selectivity against closely related kinases in the AGC and CMGC families. Moreover, 13a demonstrates potent cellular activity comparable to staurosporine, with IC(50) values of 0.42 and 0.59microM against MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of phosphorylation of the Akt downstream target GSK3 was also observed in FL5.12-Akt1 cells with an EC(50) of 1.5microM. The X-ray structures of 12 and 13a in complex with PKA in the ATP-binding site were determined. |
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