Effect of novel PKCθ selective inhibitor AS2521780 on acute rejection in rat and non-human primate models of transplantation

Selective inhibition of protein kinase Cθ (PKCθ) may be useful in inducing T cell-specific immunosuppression with a reduced rate of side effects. To our knowledge, however, no reports have been published regarding the selective inhibition of PKCθ by small-molecule compounds in animal models of allograft rejection. Here, we investigated the effect of the newly synthesized PKCθ selective inhibitor AS2521780 in mono- and combination therapies on acute rejection in ACI-to-Lewis rat cardiac and non-human primate (NHP) renal transplantation models. In the rat cardiac transplantation model, AS2521780 significantly prolonged graft survival to 14 days at 10 mg/kg twice daily (b.i.d.) and to 20 days at 30 mg/kg b.i.d. In contrast, acute rejection occurred in all recipients in the non-treated group by Days 5 or 6 post-transplantation. Significant improvements (P < 0.001) in graft survival were observed following treatment with a combination of AS2521780 at 3 mg/kg b.i.d. and a suboptimal dose of tacrolimus (0.02 mg/kg) or mycophenolate mofetil (15 mg/kg). In the NHP renal transplantation model, AS2521780 at 3 mg/kg b.i.d. and tacrolimus at 1 mg/kg (suboptimal dose) significantly improved graft survival compared to tacrolimus alone (P < 0.05). The present study of AS2521780 in rat cardiac and NHP renal transplantation models demonstrates the potential of PKCθ as a novel drug target for organ transplantation. As AS2521780 was well tolerated and the dose of tacrolimus or mycophenolate mofetil can be reduced when used in combination with this drug, immunosuppressive regimens containing selective inhibitors of PKCθ might have good safety profiles.