Design and synthesis of novel amide AKT1 inhibitors with selectivity over CDK2

Through the analysis of X-ray crystallographic information and previous SAR studies, a novel series of protein kinase B (PKB/AKT) inhibitors was developed. The compounds showed nanomolar inhibition of AKT1 and were selective against cyclin-dependent kinase 2 (CDK2).

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Bibliographic Details
Published in	Bioorganic & medicinal chemistry letters Vol. 21; no. 18; pp. 5191 - 5196
Main Authors	Ashton, Kate S., St. Jean, David J., Poon, Steve F., Lee, Matthew R., Allen, John G., Zhang, Shiwen, Lofgren, Julie A., Zhang, Xiaoling, Fotsch, Christopher, Hungate, Randall
Format	Journal Article
Language	English
Published	Amsterdam Elsevier Ltd 15.09.2011 Elsevier
Subjects	AKT amides Amides - chemical synthesis Amides - chemistry Amides - pharmacology Antineoplastic agents Biological and medical sciences Cancer CDK Chemistry Techniques, Synthetic Crystallography, X-Ray cyclin-dependent kinase Cyclin-Dependent Kinase 2 - antagonists & inhibitors Cyclin-Dependent Kinase 2 - metabolism Dose-Response Relationship, Drug Drug Design enzyme inhibitors Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology General aspects Medical sciences Models, Molecular Molecular Structure Pharmacology. Drug treatments PKB Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Stereoisomerism Structure-Activity Relationship synthesis X-ray diffraction AKT CDK PKB Cancer Rat Nitrogen heterocycle Isozyme Non-specific serine/threonine protein kinase Selectivity Modeling Cyclin-dependent kinase Signal transduction Structure activity relation Chlorine Organic compounds Piperidine derivatives Molecular model Bicyclic compound Aromatic compound Chemical synthesis Enzyme Transferases Rodentia Akt protein kinase Enzyme inhibitor Inhibitor enzyme complex In vitro In vivo Vertebrata Mammalia Animal Azetidine derivatives Carboxamide Fluorine Organic compounds
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Summary:	Through the analysis of X-ray crystallographic information and previous SAR studies, a novel series of protein kinase B (PKB/AKT) inhibitors was developed. The compounds showed nanomolar inhibition of AKT1 and were selective against cyclin-dependent kinase 2 (CDK2).
Bibliography:	http://dx.doi.org/10.1016/j.bmcl.2011.07.056 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.07.056