Pharmacological inhibitory profile of TAK-828F, a potent and selective orally available ROR gamma t inverse agonist

Shibata Akira; Uga Keiko; Sato Takayuki; Sagara Masaki; Igaki Keiko; Nakamura Yoshiki; Ochida Atsuko; Kono Mitsunori; Shirai Junya; Yamamoto Satoshi; Yamasaki Masashi; Tsuchimori Noboru

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Pharmacological inhibitory profile of TAK-828F, a potent and selective orally available ROR gamma t inverse agonist

机译：TAK-828F的药理抑制型材，一种有效和选择性口服的RORγ逆激动剂

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Retinoic acid-related orphan receptor gamma t (ROR gamma t) is a key master regulator of the differentiation and activation of IL-17 producing CD4(+) Th17, CD8(+) Tc17 and IL-17/IFN-gamma co-producing cells (Th1/17 cells). These cells play critical roles in the pathogenesis of autoimmune diseases such as inflammatory bowel disease and multiple sclerosis. Thus, ROR gamma t is an attractive target for the treatment of these diseases. We discovered TAK-828F, an orally available potent and selective ROR gamma t inverse agonist. The inhibitory effect on the activation and differentiation of Th17 cells by TAK-828F was evaluated in mouse and human primary cells. TAK-828F inhibited IL-17 production from mouse splenocytes and human peripheral blood mononuclear cells dose-dependently at concentrations of 0.01-10 mu M without affecting the production of IFN-gamma. Additionally, TAK-828F strongly inhibited Th17, Tc17 and Th1/17 cells' differentiation from naive T cells and memory CD4(+) T cells at 100 nM without affecting Th1 cells' differentiation. In addition, TAK-828F improved Th17/Treg cells' population ratio by inhibiting Th17 cells' differentiation and up-regulating Treg cells. Furthermore, TAK-828F, at 100 nM, reduced the production of Th17-related cytokines (IL-17, IL-17F and IL-22) without affecting IFN-gamma production in whole blood. These results demonstrate that TAK-828F has the potent and selective inhibitory activity against ROR gamma t both in mouse and human cells. Additionally, oral administration of TAK-828F showed promising efficacy in naive T cell transfer mouse colitis model. TAK-828F may provide a novel therapeutic option to treat immune diseases by inhibiting Th17 and Th1/17 cells' differentiation and improving imbalance between Th17 and Treg cells.

机译：与视黄酸相关的孤儿受体γT（RORγT）是IL-17的分化和活化的关键常规调节剂，其产生CD4（+）TH17，CD8（+）TC17和IL-17 / IFN-Gamma共同产生细胞（Th1 / 17细胞）。这些细胞在自身免疫疾病的发病机制中起重要作用，例如炎症性肠病和多发性硬化症。因此，RORγT是治疗这些疾病的吸引力。我们发现了TAK-828F，一个口头上有效和选择性的ROR伽玛T逆激动剂。在小鼠和人的原代细胞中评估了TAK-828F对Th17细胞活化和分化的抑制作用。 TAK-828F抑制小鼠脾细胞和人外周血单核细胞的IL-17生产依赖性在0.01-10μm的浓度下，而不影响IFN-γ的产生。另外，TAK-828F在100nm下强烈抑制Th17，Tc17和Th1 / 17细胞的分化，而不影响Th1细胞的分化。此外，TAK-828F通过抑制Th17细胞分化和上调Treg细胞来改善Th17 / Treg细胞的群体比。此外，在100nm处，Tak-828F，减少了Th17相关细胞因子（IL-17，IL-17F和IL-22）的产生，而不会影响全血的IFN-Gamma产生。这些结果表明，TAK-828F在小鼠和人细胞中具有对RORγT的有效和选择性的抑制活性。另外，塔克-828F的口服给药在幼稚T细胞转移小鼠结肠炎模型中显示出有希望的疗效。 TAK-828F可以通过抑制TH17和TH1 / 17细胞的分化并改善TH17和TREG细胞之间的不平衡来提供一种新的治疗方法来治疗免疫疾病。

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来源
《Biochemical Pharmacology》 |2018年第2018期|共11页
作者
Shibata Akira; Uga Keiko; Sato Takayuki; Sagara Masaki; Igaki Keiko; Nakamura Yoshiki; Ochida Atsuko; Kono Mitsunori; Shirai Junya; Yamamoto Satoshi; Yamasaki Masashi; Tsuchimori Noboru;
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作者单位

Takeda Pharmaceut Co Ltd Pharmaceut Res Div Immunol Unit Fujisawa Kanagawa Japan;

Takeda Pharmaceut Co Ltd Pharmaceut Res Div Immunol Unit Fujisawa Kanagawa Japan;

Takeda Pharmaceut Co Ltd Pharmaceut Res Div Immunol Unit Fujisawa Kanagawa Japan;

Takeda Pharmaceut Co Ltd Pharmaceut Res Div Immunol Unit Fujisawa Kanagawa Japan;

Takeda Pharmaceut Co Ltd Pharmaceut Res Div Immunol Unit Fujisawa Kanagawa Japan;

Takeda Pharmaceut Co Ltd Pharmaceut Res Div Immunol Unit Fujisawa Kanagawa Japan;

Takeda Pharmaceut Co Ltd Pharmaceut Res Div Med Chem Res Labs Fujisawa Kanagawa Japan;

Takeda Pharmaceut Co Ltd Pharmaceut Res Div Immunol Unit Fujisawa Kanagawa Japan;

Takeda Pharmaceut Co Ltd Pharmaceut Res Div Immunol Unit Fujisawa Kanagawa Japan;

Takeda Pharmaceut Co Ltd Pharmaceut Res Div Immunol Unit Fujisawa Kanagawa Japan;

Takeda Pharmaceut Co Ltd Pharmaceut Res Div Immunol Unit Fujisawa Kanagawa Japan;

Takeda Pharmaceut Co Ltd Pharmaceut Res Div Immunol Unit Fujisawa Kanagawa Japan;

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原文格式 PDF
正文语种 eng
中图分类药理学;
关键词
IL-17; ROR gamma t; TAK-828F; Th17; Th1/17;

机译：IL-17;ROR Gamma T;TAK-828F;TH17;TH1 / 17;

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Pharmacological inhibitory profile of TAK-828F, a potent and selective orally available ROR gamma t inverse agonist

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