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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2011-3-17
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pubmed:databankReference |
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pubmed:abstractText |
Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:AxtenJeffrey MJM,
pubmed-author:BeckerChristopher JCJ,
pubmed-author:BlackledgeCharles WCW,
pubmed-author:BobkoMark AMA,
pubmed-author:BradyPat GPG,
pubmed-author:CampobassoNinoN,
pubmed-author:ChaddertonAntony RAR,
pubmed-author:DumbleMelissaM,
pubmed-author:DuquenneCelineC,
pubmed-author:FengYanhongY,
pubmed-author:GardinerChristine MCM,
pubmed-author:GilbertSethS,
pubmed-author:GrantSeth WSW,
pubmed-author:HeerdingDirkD,
pubmed-author:IpN YNY,
pubmed-author:LiWilliam HWH,
pubmed-author:MedinaJesús RJR,
pubmed-author:MillerWilliam HWH,
pubmed-author:RabindranSridhar KSK,
pubmed-author:RomerilStuart PSP,
pubmed-author:ScherzerDarylD,
pubmed-author:ShuArthurA,
pubmed-author:SudakinValeryV,
pubmed-author:WardParisP,
pubmed-author:XiangHongH
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pubmed:issnType |
Electronic
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pubmed:day |
24
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pubmed:volume |
54
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1871-95
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pubmed:meshHeading |
pubmed-meshheading:21341675-Animals,
pubmed-meshheading:21341675-Antineoplastic Agents,
pubmed-meshheading:21341675-Cell Line, Tumor,
pubmed-meshheading:21341675-Crystallography, X-Ray,
pubmed-meshheading:21341675-Drug Screening Assays, Antitumor,
pubmed-meshheading:21341675-Indazoles,
pubmed-meshheading:21341675-Mice,
pubmed-meshheading:21341675-Mice, SCID,
pubmed-meshheading:21341675-Models, Molecular,
pubmed-meshheading:21341675-Molecular Structure,
pubmed-meshheading:21341675-Morpholines,
pubmed-meshheading:21341675-Neoplasm Transplantation,
pubmed-meshheading:21341675-Phosphorylation,
pubmed-meshheading:21341675-Piperidines,
pubmed-meshheading:21341675-Protein Binding,
pubmed-meshheading:21341675-Protein-Serine-Threonine Kinases,
pubmed-meshheading:21341675-Pyrimidines,
pubmed-meshheading:21341675-Stereoisomerism,
pubmed-meshheading:21341675-Structure-Activity Relationship,
pubmed-meshheading:21341675-Transplantation, Heterologous
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pubmed:year |
2011
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pubmed:articleTitle |
Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors.
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pubmed:affiliation |
Oncology Research, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States. jesus.r.medina@gsk.com
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pubmed:publicationType |
Journal Article
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