title: Oral administration of a novel RORγt antagonist attenuates psoriasis-like skin lesion of two independent mouse models through neutralization of IL-17.
abstract: BACKGROUND
  Targeting the IL-17 pathway represents a highly effective strategy for the treatment of psoriasis, using antibodies against IL-17A and IL-17 receptor, suggesting that Th17 cells essentially contribute to development of psoriasis. Th17 differentiation depends on the key transcription factor, RORγt.
  
  
  OBJECTIVE
  To develop a novel RORγt antagonist which is effective on psoriasis via oral administration.
  
  
  METHODS
  A chemical library was screened using cell-based high-throughput methods, luciferase reporter assay, competitive binding assay, and T cell differentiation assay. To evaluate in vivo effects of a novel RORγt antagonist, A213, we orally administrated it to two independent mouse models of psoriasis; IL-23-injection model and K5.Stat3C transgenic mouse.
  
  
  RESULTS
  Oral administration of A213 resulted in attenuation of skin inflammation in the both mouse models. At the same time, increased levels of IL-17A expression were significantly reduced in the skin lesions and skin-draining lymph nodes.
  
  
  CONCLUSIONS
  These results implicate a new therapeutic application of RORγt antagonist for the treatment of psoriasis.
authors.affiliation: Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
authors.forename: Mikiro
authors.initials: M
authors.lastname: Takaishi
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ishizaki
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Isobe
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan.
authors.forename: Takaichi
authors.initials: T
authors.lastname: Shimozato
authors.affiliation: Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan. Electronic address: sano.derma@kochi-u.ac.jp.
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Sano
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D011565:Psoriasis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D053722:Receptors, Interleukin-17; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000633:toxicity; D058504:Th17 Cells / Q000502:physiology
chemical_list: C098680:Il17a protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D053722:Receptors, Interleukin-17; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D013755:Tetradecanoylphorbol Acetate
keywords: Antagonist; Mouse model; Psoriasis; RORγt; Th17