Mikiro Takaishi1, Masayuki Ishizaki2, Keisuke Suzuki3, Takashi Isobe2, Takaichi Shimozato2, Shigetoshi Sano4. 1. Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan. 2. Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan. 3. Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan. 4. Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan. Electronic address: sano.derma@kochi-u.ac.jp.
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. CONCLUSION: These results implicate a new therapeutic application of RORγt antagonist for the treatment of psoriasis.
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. CONCLUSION: These results implicate a new therapeutic application of RORγt antagonist for the treatment of psoriasis.
Authors: Gregory S Whitehead; Hong Soon Kang; Seddon Y Thomas; Alexander Medvedev; Tadeusz P Karcz; Gentaro Izumi; Keiko Nakano; Sergei S Makarov; Hideki Nakano; Anton M Jetten; Donald N Cook Journal: JCI Insight Date: 2019-06-11