title: Effect of AS2521780, a novel PKCθ selective inhibitor, on T cell-mediated immunity.
abstract: T cell-mediated immunity is central to the pathogenesis of autoimmune diseases, and is a target in the development of alternative therapeutic strategies with reduced adverse effects on other cell types and organs. Protein kinase C (PKC) is a family of serine/threonine kinases, with knockout of the PKCθ isoform in mice resulting in defective T cell activation. However, the effects of selective inhibition of PKCθ by small-molecule compounds on T cell signaling are still unknown. Here, we evaluated the effect of the novel PKCθ inhibitor AS2521780 on T cell activation and joint inflammation in a rat model of arthritis. AS2521780 exerted potent inhibition of recombinant human PKCθ enzyme activity (IC50=0.48 nM), which was more than 30-fold higher than that of other PKC isoforms. Further, AS2521780 exerted little or no inhibition on other protein kinases. AS2521780 suppressed CD3/CD28-induced Interleukin-2 (IL-2) gene transcription in Jurkat T cells and proliferation of human primary T cells. AS2521780 also suppressed concanavalin A-induced cytokine production by rat splenocytes and monkey peripheral blood mononuclear cells with similar potency. Moreover, AS2521780 significantly reduced paw swelling in a dose-dependent manner in a rat model of adjuvant-induced arthritis. These results indicate that PKCθ is an attractive drug target and AS2521780 is a potential immunosuppressant for T cell-mediated autoimmune diseases.
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: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki, 305-8585, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Matsuoka
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki, 305-8585, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Research Portfolio & Science, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki, 305-8585, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Medicinal Chemistry Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki, 305-8585, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka
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
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*
chemical_list: C000600437:AS2521780; D016207:Cytokines; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011493:Protein Kinase C; D000218:Adamantane
keywords: Adjuvant-induced arthritis model; CD3/CD28; Concanavalin A; Inhibitor; Interleukin-2; PKCθ