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Pharmacological Evaluation of TAK-828F, a Novel Orally Available RORγt Inverse Agonist, on Murine Colitis Model

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Abstract

IL-17-producing Th17 cells and IFN-γ and IL-17 double-producing Th1/17 cells have been identified as the pathogenic cells in inflammatory bowel disease (IBD). Retinoic acid-related orphan receptor γt (RORγt) is a master regulator for the differentiation and activation of Th17 and Th1/17 cells. We discovered a novel orally available TAK-828F, a strong and selective RORγt inverse agonist. To assess the potential of RORγt blockade in the therapy for IBD, the efficacy of TAK-828F in activated T cell transfer mouse colitis model was investigated. This model was highly sensitive to the prophylactic treatment of anti-TNF-α monoclonal antibody but partially susceptible to sulfasalazine, tacrolimus, and prednisolone. Oral administration of TAK-828F, at doses of 1 and 3 mg/kg, b.i.d, strongly protected the progression of colitis. TAK-828F decreased the population of Th17 and Th1/17 cells in a dose-dependent manner in the mesenteric lymph node. Moreover, expression of mRNA that are characteristic of the Th17 signature, such as IL-17A and IL-17F in the colon, were inhibited by TAK-828F, while the expression of IL-10, an anti-inflammatory cytokine, was increased. In the therapeutic treatment, TAK-828F lessened disease severity compared to the vehicle control mice. Interestingly, gene expression of zonula occludens-1 (ZO-1) and mucin 2 (Muc2), which play an important role in barrier function of the intestinal mucosa, was recovered by TAK-828F. These results indicate that blocking RORγt has promising pharmacological profile in the colitis model. RORγt blockade may provide a novel therapeutic paradigm for treatment of IBD with unique mechanism by which improves imbalance of the immune system.

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Acknowledgments

The authors thank the following employees of Takeda Pharmaceutical Company Ltd.: Yasushi Fujitani, Chihiro Akimoto, Keiko Koga and Keiko Ishigami, and Hikaru Saitou for their contribution to pharmacological studies and discussion and Tsuneo Oda, Atsuko Ochida, Mitsunori Kono, Junya Shirai, and Satoshi Yamamoto for their contribution to compound synthesis.

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  1. Keiko Igaki, Keiko Uga & Masashi Yamasaki

    Present address: Axcelead Drug Discovery Partners, Inc., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan

  2. Yoshiki Nakamura

    Present address: Pharmaceutical Sciences, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan

Authors and Affiliations

  1. Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan

    Keiko Igaki, Yoshiki Nakamura, Yusaku Komoike, Keiko Uga, Akira Shibata, Masashi Yamasaki & Noboru Tsuchimori

  2. Drug safety Research Laboratories, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan

    Yoshimasa Ishimura

  3. Gastrointestinal Drug Discovery Unit, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan

    Yasuhiro Tsukimi

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  1. Keiko Igaki
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Igaki, K., Nakamura, Y., Komoike, Y. et al. Pharmacological Evaluation of TAK-828F, a Novel Orally Available RORγt Inverse Agonist, on Murine Colitis Model. Inflammation 42, 91–102 (2019). https://doi.org/10.1007/s10753-018-0875-7

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