The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation

J Pharmacol Exp Ther. 2009 Sep;330(3):792-801. doi: 10.1124/jpet.109.153205. Epub 2009 Jun 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD28 Antigens / metabolism
  • Calcium / metabolism
  • Cell Adhesion / drug effects
  • Cytokines / biosynthesis
  • Electrophoretic Mobility Shift Assay
  • Flow Cytometry
  • Genes, Reporter
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Jurkat Cells
  • Macrophage Activation / drug effects*
  • Mice
  • Mice, Knockout
  • NF-kappa B / drug effects
  • NFATC Transcription Factors / metabolism
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C / genetics
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrroles / antagonists & inhibitors*
  • Quinazolines / antagonists & inhibitors*
  • Receptors, Antigen, T-Cell / drug effects
  • Signal Transduction / drug effects
  • T-Lymphocytes / drug effects*


  • CD28 Antigens
  • Cytokines
  • Immunosuppressive Agents
  • Isoenzymes
  • NF-kappa B
  • NFATC Transcription Factors
  • Protein Kinase Inhibitors
  • Pyrroles
  • Quinazolines
  • Receptors, Antigen, T-Cell
  • sotrastaurin
  • Protein Kinase C
  • Calcium