title: Effect of novel PKCθ selective inhibitor AS2521780 on acute rejection in rat and non-human primate models of transplantation.
abstract: 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 14days at 10mg/kg twice daily (b.i.d.) and to 20days at 30mg/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 3mg/kg b.i.d. and a suboptimal dose of tacrolimus (0.02mg/kg) or mycophenolate mofetil (15mg/kg). In the NHP renal transplantation model, AS2521780 at 3mg/kg b.i.d. and tacrolimus at 1mg/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.
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. Electronic address: hidehiko.fukahori@astellas.com.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Fukahori
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Chida
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tasaki
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kawashima
authors.affiliation: Drug Safety Research Labs, Drug Discovery Research, Astellas Pharma Inc., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noto
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Tsujimoto
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Oshima
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hirose
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Morokata
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D006084:Graft Rejection / Q000188:drug therapy*; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D016030:Kidney Transplantation; D008252:Macaca fascicularis; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000627:therapeutic use
chemical_list: C000600437:AS2521780; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011493:Protein Kinase C; D009173:Mycophenolic Acid; D000218:Adamantane; D016559:Tacrolimus
keywords: Combination therapy; Monotherapy; Mycophenolate mofetil; PKCθ; Tacrolimus; Transplantation