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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

2006; Elsevier BV; Volume: 16; Issue: 7 Linguagem: Inglês

10.1016/j.bmcl.2005.12.065

1464-3405

Qun Li, Keith W. Woods, Sheela A. Thomas, Gui‐Dong Zhu, Garrick K. Packard, John P. Fisher, Tongmei Li, Jianchun Gong, Jürgen Dinges, Xiaohong Song, Jason N. Abrams, Yan Luo, Eric F. Johnson, Yan Shi, Xuesong Liu, Vered Klinghofer, Ron Des Jong, Tilman Oltersdorf, Vincent S. Stoll, Clarissa G. Jakob, Saul H. Rosenberg, Vincent L. Giranda,

Synthesis and biological activity

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 IC50 of 1.3 nM 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 IC50 values of 0.42 and 0.59 μM 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 EC50 of 1.5 μM. The X-ray structures of 12 and 13a in complex with PKA in the ATP-binding site were determined.