title: The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation.
abstract: 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.
authors.affiliation: Novartis Institute for BioMedical Research, WSJ-386.5.27, CH-4002 Basel, Switzerland. jeanpierre.evenou@novartis.com
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Evenou
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wagner
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zenke
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
authors.forename: Kathrin
authors.initials: K
authors.lastname: Wagner
authors.forename: Jiri
authors.initials: J
authors.lastname: Kovarik
authors.forename: Karl A
authors.initials: KA
authors.lastname: Welzenbach
authors.forename: Gabriele
authors.initials: G
authors.lastname: Weitz-Schmidt
authors.forename: Christine
authors.initials: C
authors.lastname: Guntermann
authors.forename: Harry
authors.initials: H
authors.lastname: Towbin
authors.forename: Sylvain
authors.initials: S
authors.lastname: Cottens
authors.forename: Sandra
authors.initials: S
authors.lastname: Kaminski
authors.forename: Thomas
authors.initials: T
authors.lastname: Letschka
authors.forename: Christina
authors.initials: C
authors.lastname: Lutz-Nicoladoni
authors.forename: Thomas
authors.initials: T
authors.lastname: Gruber
authors.forename: Natascha
authors.initials: N
authors.lastname: Hermann-Kleiter
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Thuille
authors.forename: Gottfried
authors.initials: G
authors.lastname: Baier
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D017930:Genes, Reporter; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D019169:Jurkat Cells; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000187:drug effects; D050778:NFATC Transcription Factors / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000037:antagonists & inhibitors*; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects*
chemical_list: D018106:CD28 Antigens; D016207:Cytokines; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; D011948:Receptors, Antigen, T-Cell; C543528:sotrastaurin; D011493:Protein Kinase C; D002118:Calcium