The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation.
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.
Evenou
Jean-Pierre
JP
Novartis Institute for BioMedical Research, WSJ-386.5.27, CH-4002 Basel, Switzerland. jeanpierre.evenou@novartis.com
Wagner
Jürgen
J
Zenke
Gerhard
G
Brinkmann
Volker
V
Wagner
Kathrin
K
Kovarik
Jiri
J
Welzenbach
Karl A
KA
Weitz-Schmidt
Gabriele
G
Guntermann
Christine
C
Towbin
Harry
H
Cottens
Sylvain
S
Kaminski
Sandra
S
Letschka
Thomas
T
Lutz-Nicoladoni
Christina
C
Gruber
Thomas
T
Hermann-Kleiter
Natascha
N
Thuille
Nikolaus
N
Baier
Gottfried
G
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*
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