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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2009-8-21
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pubmed:abstractText |
There is a pressing need for immunosuppressants with an improved safety profile. The search for novel approaches to blocking T-cell activation led to the development of the selective protein kinase C (PKC) inhibitor AEB071 (sotrastaurin). In cell-free kinase assays AEB071 inhibited PKC, with K(i) values in the subnanomolar to low nanomolar range. Upon T-cell stimulation, AEB071 markedly inhibited in situ PKC catalytic activity and selectively affected both the canonical nuclear factor-kappaB and nuclear factor of activated T cells (but not activator protein-1) transactivation pathways. In primary human and mouse T cells, AEB071 treatment effectively abrogated at low nanomolar concentration markers of early T-cell activation, such as interleukin-2 secretion and CD25 expression. Accordingly, the CD3/CD28 antibody- and alloantigen-induced T-cell proliferation responses were potently inhibited by AEB071 in the absence of nonspecific antiproliferative effects. Unlike former PKC inhibitors, AEB071 did not enhance apoptosis of murine T-cell blasts in a model of activation-induced cell death. Furthermore, AEB071 markedly inhibited lymphocyte function-associated antigen-1-mediated T-cell adhesion at nanomolar concentrations. The mode of action of AEB071 is different from that of calcineurin inhibitors, and AEB071 and cyclosporine A seem to have complementary effects on T-cell signaling pathways.
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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 |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD28,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Cytokines,
http://linkedlifedata.com/resource/pubmed/chemical/Immunosuppressive Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B,
http://linkedlifedata.com/resource/pubmed/chemical/NFATC Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase C,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrroles,
http://linkedlifedata.com/resource/pubmed/chemical/Quinazolines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Antigen, T-Cell
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
1521-0103
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pubmed:author |
pubmed-author:BaierGottfriedG,
pubmed-author:BrinkmannVolkerV,
pubmed-author:CottensSylvainS,
pubmed-author:EvenouJean-PierreJP,
pubmed-author:GruberThomasT,
pubmed-author:GuntermannChristineC,
pubmed-author:Hermann-KleiterNataschaN,
pubmed-author:KaminskiSandraS,
pubmed-author:KovarikJiriJ,
pubmed-author:LetschkaThomasT,
pubmed-author:Lutz-NicoladoniChristinaC,
pubmed-author:ThuilleNikolausN,
pubmed-author:TowbinHarryH,
pubmed-author:WagnerJürgenJ,
pubmed-author:WagnerKathrinK,
pubmed-author:Weitz-SchmidtGabrieleG,
pubmed-author:WelzenbachKarl AKA,
pubmed-author:ZenkeGerhardG
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pubmed:issnType |
Electronic
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pubmed:volume |
330
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
792-801
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pubmed:meshHeading |
pubmed-meshheading:19491325-Animals,
pubmed-meshheading:19491325-Antigens, CD28,
pubmed-meshheading:19491325-Calcium,
pubmed-meshheading:19491325-Cell Adhesion,
pubmed-meshheading:19491325-Cytokines,
pubmed-meshheading:19491325-Electrophoretic Mobility Shift Assay,
pubmed-meshheading:19491325-Flow Cytometry,
pubmed-meshheading:19491325-Genes, Reporter,
pubmed-meshheading:19491325-Humans,
pubmed-meshheading:19491325-Immunosuppressive Agents,
pubmed-meshheading:19491325-Isoenzymes,
pubmed-meshheading:19491325-Jurkat Cells,
pubmed-meshheading:19491325-Macrophage Activation,
pubmed-meshheading:19491325-Mice,
pubmed-meshheading:19491325-Mice, Knockout,
pubmed-meshheading:19491325-NF-kappa B,
pubmed-meshheading:19491325-NFATC Transcription Factors,
pubmed-meshheading:19491325-Protein Kinase C,
pubmed-meshheading:19491325-Protein Kinase Inhibitors,
pubmed-meshheading:19491325-Pyrroles,
pubmed-meshheading:19491325-Quinazolines,
pubmed-meshheading:19491325-Receptors, Antigen, T-Cell,
pubmed-meshheading:19491325-Signal Transduction,
pubmed-meshheading:19491325-T-Lymphocytes
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pubmed:year |
2009
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pubmed:articleTitle |
The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation.
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pubmed:affiliation |
Novartis Institute for BioMedical Research, WSJ-386.5.27, CH-4002 Basel, Switzerland. jeanpierre.evenou@novartis.com
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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