Arita Kojo, Tao Haiyan, Crowe Paul, Thacher Scott, Otake Sho, Kobayashi Kazuma, Ebihara Shin, Okamoto Yoshihisa, Katsuda Yoshiaki, Yamaguchi Takayuki, Matsushita Mutsuyoshi
Central Pharmaceutical Research Institute, Japan Tobacco Inc.
Orphagen Pharmaceuticals, Inc.
Biol Pharm Bull. 2024;47(12):2050-2057. doi: 10.1248/bpb.b24-00490.
Retinoid-related orphan receptor-γ (RORγ) is a nuclear receptor that plays important roles in the development and activation of T helper type-17 (Th17) cells. In this study, we characterized the pharmacological profile of JTE-151 ((4S)-6-[(2-chloro-4-methylphenyl)amino]-4-{4-cyclopropyl-5-[cis-3-(2,2-dimethylpropyl)cyclobutyl]isoxazol-3yl}-6-oxohexanoic acid), which is a novel RORγ antagonist identified by our group. JTE-151 dissociated co-activator peptide from the human RORγ-ligand binding domain (LBD) and recruited co-repressor peptide into human RORγ-LBD, and potently inhibited the transcriptional activity of RORγ of human, mouse and rat. JTE-151 also demonstrated high selectivity against other receptors in nuclear receptor family. JTE-151 suppressed the differentiation of mouse naïve CD4 T cells into Th17 cells without affecting the differentiation of those cells into other CD4 T cell subsets in vitro. In addition, JTE-151 inhibited the production of interleukin-17 (IL-17) but not interferon-γ (IFN-γ) and IL-4 from activated human helper T cells in vitro. Furthermore, treatment with JTE-151 suppressed the production of IL-17 in antigen-sensitized mice and ameliorated the severity of arthritis in mice with collagen-induced arthritis regardless of treatment start date. Based on these results, we reasoned that JTE-151 could serve as a novel therapeutic compound for various autoimmune diseases linked to Th17 cells, such as psoriasis and rheumatoid arthritis.
维甲酸相关孤儿受体γ（RORγ）是一种核受体，在辅助性T细胞17（Th17）细胞的发育和激活中发挥重要作用。在本研究中，我们对JTE - 151（(4S)-6-[(2-氯-4-甲基苯基)氨基]-4-{4-环丙基-5-[顺式-3-(2,2-二甲基丙基)环丁基]异恶唑-3-基}-6-氧代己酸）的药理特性进行了表征，它是我们团队鉴定出的一种新型RORγ拮抗剂。JTE - 151使人RORγ配体结合域（LBD）与共激活肽解离，并将共抑制肽募集到人RORγ - LBD中，有力地抑制了人、小鼠和大鼠RORγ的转录活性。JTE - 151对核受体家族中的其他受体也表现出高选择性。JTE - 151在体外抑制小鼠初始CD4 T细胞向Th17细胞的分化，而不影响这些细胞向其他CD4 T细胞亚群的分化。此外，JTE - 151在体外抑制活化的人辅助性T细胞产生白细胞介素-17（IL - 17），但不抑制干扰素-γ（IFN - γ）和IL - 4的产生。此外，用JTE - 151治疗可抑制抗原致敏小鼠中IL - 17的产生，并改善胶原诱导性关节炎小鼠的关节炎严重程度，且与治疗开始日期无关。基于这些结果，我们推断JTE - 151可作为一种新型治疗化合物，用于治疗与Th17细胞相关的各种自身免疫性疾病，如银屑病和类风湿性关节炎。
