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rdf:type |
|
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lifeskim:mentions |
umls-concept:C0006826,
umls-concept:C0038477,
umls-concept:C0087111,
umls-concept:C0164786,
umls-concept:C0220781,
umls-concept:C0285558,
umls-concept:C0812228,
umls-concept:C1705328,
umls-concept:C1705341,
umls-concept:C1880355,
umls-concept:C1883254,
umls-concept:C1999216
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pubmed:issue |
7
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|
pubmed:dateCreated |
2006-2-27
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|
pubmed:abstractText |
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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pubmed:language |
eng
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pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
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pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Apr
|
|
pubmed:issn |
0960-894X
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|
pubmed:author |
pubmed-author:AbramsJasonJ,
pubmed-author:ChuI YIY,
pubmed-author:Des JongRonR,
pubmed-author:DingesJurgenJ,
pubmed-author:FisherJohnJ,
pubmed-author:GirandaVincent LVL,
pubmed-author:GongJianchunJ,
pubmed-author:JakobClarissa GCG,
pubmed-author:JohnsonEric FEF,
pubmed-author:KlinghoferVeredV,
pubmed-author:LiQunQ,
pubmed-author:LiTongmeiT,
pubmed-author:LiuXuesongX,
pubmed-author:LuoYanY,
pubmed-author:OltersdorfTilmanT,
pubmed-author:PackardGarrickG,
pubmed-author:RosenbergSaul HSH,
pubmed-author:SongXiaohongX,
pubmed-author:StollVincent SVS,
pubmed-author:ThomasSheelaS,
pubmed-author:WoodsKeith WKW,
pubmed-author:ZhuGui-DongGD
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|
pubmed:issnType |
Print
|
|
pubmed:day |
1
|
|
pubmed:volume |
16
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
2000-7
|
|
pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:16413780-Antineoplastic Agents,
pubmed-meshheading:16413780-Cell Line,
pubmed-meshheading:16413780-Hydrogen Bonding,
pubmed-meshheading:16413780-Models, Molecular,
pubmed-meshheading:16413780-Neoplasms,
pubmed-meshheading:16413780-Protein Kinase Inhibitors,
pubmed-meshheading:16413780-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:16413780-Pyridines,
pubmed-meshheading:16413780-Structure-Activity Relationship,
pubmed-meshheading:16413780-X-Ray Diffraction
|
|
pubmed:year |
2006
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|
pubmed:articleTitle |
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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pubmed:affiliation |
Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. qun.li@abbott.com
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pubmed:publicationType |
Journal Article
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