TY - JOUR T1 - The Potent Protein Kinase C-Selective Inhibitor AEB071 (Sotrastaurin) Represents a New Class of Immunosuppressive Agents Affecting Early T-Cell Activation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 792 LP - 801 DO - 10.1124/jpet.109.153205 VL - 330 IS - 3 AU - Jean-Pierre Evenou AU - Jürgen Wagner AU - Gerhard Zenke AU - Volker Brinkmann AU - Kathrin Wagner AU - Jiri Kovarik AU - Karl A. Welzenbach AU - Gabriele Weitz-Schmidt AU - Christine Guntermann AU - Harry Towbin AU - Sylvain Cottens AU - Sandra Kaminski AU - Thomas Letschka AU - Christina Lutz-Nicoladoni AU - Thomas Gruber AU - Natascha Hermann-Kleiter AU - Nikolaus Thuille AU - Gottfried Baier Y1 - 2009/09/01 UR - http://jpet.aspetjournals.org/content/330/3/792.abstract N2 - 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 Ki values in the subnanomolar to low nanomolar range. Upon T-cell stimulation, AEB071 markedly inhibited in situ PKCθ catalytic activity and selectively affected both the canonical nuclear factor-κB 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. The American Society for Pharmacology and Experimental Therapeutics ER -