当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY LETTERS期刊下所有文献 > 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.

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.

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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Li Q,Woods KW,Thomas S,Zhu GD,Packard G,Fisher J,Li T,Gong J,Dinges J,Song X,Abrams J,Luo Y,Johnson EF,Shi Y,Liu X,Klinghofer V,Des Jong R,Oltersdorf T,Stoll VS,Jakob CG,Rosenberg SH,Giranda VL

doi

10.1016/j.bmcl.2005.12.065

subject

Has Abstract

pub_date

2006-04-01 00:00:00

pages

2000-7

issue

7

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(05)01634-3

journal_volume

16

pub_type

杂志文章

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