Effects of the novel protein kinase C inhibitor AEB071 (Sotrastaurin) on rat cardiac allograft survival using single agent treatment or combination therapy with cyclosporine, everolimus or FTY720

Abstract

Summary NVP‐AEB071 (AEB, sotrastaurin), an oral inhibitor of protein kinase C (PKC), effectively blocks T‐cell activation. The immunosuppressive effects of oral AEB were demonstrated in a rat local graft versus host (GvH) reaction and rat cardiac transplantation models. T‐cell activation was suppressed by 95% in blood from AEB‐treated rats, with a positive correlation between T‐cell inhibition and AEB blood concentration. In GvH studies, AEB inhibited lymph node swelling dose‐dependently (3–30 mg/kg). BN and DA cardiac allografts were acutely rejected within 6–10 days post‐transplantation in untreated LEW rats. AEB at 10 and 30 mg/kg b.i.d. prolonged BN graft survival to a mean survival time of 15 and >28 days, and DA grafts to 6.5 and 17.5 days, respectively. In the DA to LEW model, combining a nonefficacious dose of AEB (10 mg/kg b.i.d.) with a nonefficacious dose of cyclosporine, everolimus or FTY720 led to prolonged median survival times (26 days, >68 days and >68 days, respectively). Pharmacokinetic monitoring excluded drug–drug interactions, suggesting synergy. In conclusion, these studies are the first to demonstrate that AEB prolongs rat heart allograft survival safely as monotherapy and in combination with nonefficacious doses of cyclosporine, everolimus or FTY720. Thus, AEB may have the potential to offer an alternative to calcineurin inhibitor‐based therapies.

The Effects of AEB071 (Sotrastaurin) with Tacrolimus on Rat Heterotopic Cardiac Allograft Rejection and Survival

“…Taken together, these results suggest that AEB071 combination therapy with lower dose of Tac enhances allograft survival compared with higher dose Tac monotherapy groups in a BN-to-LEW rat heterotopic cardiac transplant model. Moreover, these results are in agreement with the data presented in a recent review by Weckbecker et al [14], on AEB071 combination therapy with CsA, everolimus or FTT720. In the heart graft histology, AEB071 monotherapy seemed to decrease inflammatory cell infiltration of the graft.…”

“…Rats that survived 30 d did not receive any further administrations. The AEB071 and Tac combination treatments were administered at 30-minute intervals, with AEB071 always administered initially [13,14].…”

Protein Kinase C Inhibitor Sotrastaurin Selectively Inhibits the Growth of CD79 Mutant Diffuse Large B-Cell Lymphomas

“…This model suggested that cells with tonic BCR signaling may also be sensitive to PKCb inhibition, as this kinase is a critical mediator of CBM complex activation downstream of SYK (9,10). We therefore evaluated the effects of 2 ATP-competitive PKC inhibitors, the pan-PKC inhibitor STN (18,(20)(21)(22) and the PKCa/b-selective compound BHA536 (Novartis; unpublished, see structure and selectivity data in Supplementary Fig. S1) on the proliferation of a panel of DLBCL cell lines.…”

Effect of AS2521780, a novel PKCθ selective inhibitor, on T cell-mediated immunity

“…AEB071 (sotrastaurin) is a first-in-class, orally active and selective PKC inhibitor. This compound strongly inhibits PKCθ (Evenou et al, 2009), and prevents allograft rejection in both rat and nonhuman primate models of transplantation (Bigaud et al, 2012;Fang et al, 2011;Weckbecker et al, 2010). Further, immunosuppression via AEB071 has been confirmed in clinical trials for anti-rejection therapy after kidney transplantation (Russ et al, 2013).…”