高橋　恭子 (タカハシ　キョウコ)

Takahashi, Kyoko

写真a

所属（所属キャンパス）

薬学部 薬科学科 医薬品化学講座 （芝共立）

職名

専任講師

メールアドレス

メールアドレス

外部リンク
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学歴 【 表示 ／ 非表示 】

  • 1986年03月

    共立薬科大学, 薬学部

    大学, 卒業

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学位 【 表示 ／ 非表示 】

  • 博士（薬学）, 共立薬科大学, 論文, 2007年12月

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研究分野 【 表示 ／ 非表示 】

  • 化学系薬学

  • 創薬化学

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研究テーマ 【 表示 ／ 非表示 】

  • パーキンソン病治療薬の創製, 

    2012年
    -
    継続中

  • 抗酸化活性化合物の合成とデザイン, 

    2002年04月
    -
    継続中

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著書 【 表示 ／ 非表示 】

  • Interprofessional Education at the Keio University Faculty of Pharmacy, in: Advanced Initiatives in Interprofessional Education in Japan" (ed. by Watanabe H, Koizumi M)."

    Ehara Y, Abe Y, Fujimoto K, Fukushima N, Iijima S, Ishikawa S, Kishimoto K, Mochizuki M, Takahashi K, Yokota E, Kobayashi S., Springer, Tokyo, Berlin, Heidelberg, New York, 2010年02月

    担当範囲: pp57-63

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論文 【 表示 ／ 非表示 】

  • A 5-hydroxyoxindole derivative attenuates LPS-induced inflammatory responses by activating the p38-Nrf2 signaling axis

    Niino Tomomi, Tago Kenji, Yasuda Daisuke, Takahashi Kyoko, Mashino Tadahiko, Tamura Hiroomi, Funakoshi-Tago Megumi

    Biochemical Pharmacology 155   182 - 197 2018年09月

    ISSN  0006-2952

    　概要を見る

    <p>5-Hydroxyoxindole is a urinary metabolite of indole that exhibits antioxidant activity. In the present study, we found that a 5-hydroxyoxindole derivative (5-HI) significantly inhibited LPS-induced inflammatory effects in the murine macrophage cell line, RAW264.7. 5-HI induced the expression of the transcription factor, Nrf2, which is typically ubiquitinated by Keap1, an adaptor component of the ubiquitin E3 ligase complex, resulting in its proteasomal degradation. By utilizing Keap1−/− MEFs reconstituted with Keap1 mutants harboring substitutions in their major cysteine residues, we clarified the importance of Cys151 in Keap1 as a sensor for 5-HI in the induction of Nrf2 expression. Furthermore, 5-HI induced the activation of the MKK3/6-p38 pathway, which is required for the transcriptional activation of Nrf2. The knockdown of Nrf2 enhanced the LPS-induced expression of inflammatory mediators, including iNOS, NO, and CCL2, and effectively repressed the inhibitory effects of 5-HI on their expression. Although 5-HI and antioxidant N-acetyl cysteine (NAC) both reduced LPS-induced ROS generation, the treatment with NAC did not affect the LPS-induced expression of inflammatory mediators, suggesting that the anti-inflammatory activity of 5-HI mediated by Nrf2 is independent of redox control. Furthermore, when injected into mice with 5-HI, the expression of Nrf2 was significantly increased, and the LPS-induced mRNA expression of CXCL1, CCL2, TNFα and IL-6 were remarkably inhibited in the kidneys, liver, and lungs, and the production of these cytokines in serum was effectively reduced. Collectively, these results suggest that 5-HI has potential in the treatment of inflammatory diseases through the activation of Nrf2.</p>

  • Hit-to-Lead in Academia

    Yasuda Daisuke, Obata Rika, Takahashi Kyoko, Ohe Tomoyuki, Mashino Tadahiko

    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 138 （ 8 ） 1059 - 1065 2018年01月

    ISSN  0031-6903

    　概要を見る

    <p> In the process of recent hit-to-lead studies, not only in industry but also in academia, early evaluation of metabolic properties has been one of the key aspects supporting a higher probability of success in drug discovery. In this review, we introduce the development of chemical seeds targeting the Kelch-like ECH-associated protein-1 (Keap1) as an example of an academic hit-to-lead study considering metabolic stability. Keap1 regulates the function of nuclear factor erythroid 2-related factor 2 (Nrf2), which induces various antioxidative or detoxification proteins. An inhibitor of protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 is expected to be a novel target for drug discovery. However, Nrf2 is also activated in several cancers, such as human hepatocellular carcinoma, and causes chemoresistance, which is mediated by phosphorylated p62/Sqstm1 (p-p62), an autophagy-related protein that also undergoes a PPI with Keap1. In this case, an Nrf2 suppressor could be used to attenuate drug resistance. We discovered inhibitors against the Nrf2-Keap1 PPI and p-p62-Keap1 PPI using high-throughput screening and established the synthetic routes for the hit compounds and their derivatives. Furthermore, we assessed the metabolic stability of both of the PPI inhibitors in human liver microsomes and identified the metabolic sites.</p>

  • Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor

    Yasuda Daisuke, Yuasa Akihiro, Obata Rika, Nakajima Mao, Takahashi Kyoko, Ohe Tomoyuki, Ichimura Yoshinobu, Komatsu Masaaki, Yamamoto Masayuki, Imamura Riyo, Kojima Hirotatsu, Okabe Takayoshi, Nagano Tetsuo, Mashino Tadahiko

    Bioorganic and Medicinal Chemistry Letters 27 （ 22 ） 5006 - 5009 2017年11月

    ISSN  0960-894X

    　概要を見る

    <p>The Keap1-Nrf2 system is an attractive target for drug discovery regarding various unmet medical needs. Only covalent inhibitors for protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 have been approved or are under clinical trials, but such electrophilic compounds lack selectivity. Therefore, specific non-covalent Keap1-Nrf2 PPI inhibitors are expected to be safer Nrf2 activators. We found a novel class of non-covalent Keap1-Nrf2 PPI inhibitor that has a benzo[g]indole skeleton and an indole-3-hydroxamic acid moiety and that exhibits significant PPI inhibitory activity. Additionally, the benzo[g]indole-3-carbohydrazide derivatives were newly prepared. The benzo[g]indole derivatives showed a stronger Keap1-Nrf2 PPI inhibitory activity than Cpd16, a previously reported non-covalent PPI inhibitor. Moreover, most of the PPI inhibitors showed a high metabolic stability in a human microsome system with a low cytotoxicity against HepG2 cell lines, which suggests that novel benzo[g]indole-type Keap1-Nrf2 PPI inhibitors are expected to be biological tools or lead compounds for Nrf2 activators.</p>

  • Strategic drug design to avoid the metabolic activation of hepatotoxic drugs

    Ohe Tomoyuki, Takahashi Kyoko, Nakamura Shigeo, Mashino Tadahiko

    Yakugaku Zasshi 137 （ 3 ） 249 - 255 2017年

    ISSN  0031-6903

    　概要を見る

    <p>Adverse reactions are one of the most important issues in drug development, as well as in the therapeutic usage of drugs during the post-approval stage. Specifically, idiosyncratic adverse drug reactions (IDR) occur in only a small group of patients who are treated with certain drugs, and are unpredictable. It is widely accepted that drug-induced IDR is often associated with CYP-mediated bioactivation. Benzbromarone (BBR) is effective in the treatment of hyperuricemia, and has been used as an effective drug in Japan for a long time. However, BBR has been associated with hepatotoxicity, including fatal liver injury. We identified 2,6-dibromohydroquinone (DBH) and mono-debrominated catechol (CAT) as novel metabolites of BBR in human and rat liver microsomal systems, by comparison with chemically synthesized authentic compounds via ipso-substitution, which we previously discovered to be a unique metabolic reaction of substituted phenols by CYP. Furthermore, CAT, DBH and the oxidized form of DBH (DBBQ) were highly cytotoxic in human hepatocellular carcinoma cells, compared with BBR. We consider that the formation of these metabolites from BBR is linked to the mechanism involved in BBR-induced hepatotoxicity because catechols, hydroquinones, and their oxidized forms are known to be toxic.</p>

  • Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity

    Yasuda Daisuke, Nakajima Mao, Yuasa Akihiro, Obata Rika, Takahashi Kyoko, Ohe Tomoyuki, Ichimura Yoshinobu, Komatsu Masaaki, Yamamoto Masayuki, Imamura Riyo, Kojima Hirotatsu, Okabe Takayoshi, Nagano Tetsuo, Mashino Tadahiko

    Bioorganic and Medicinal Chemistry Letters 26 （ 24 ） 5956 - 5959 2016年12月

    ISSN  0960-894X

    　概要を見る

    <p>The Keap1-Nrf2 system is involved not only in biological defense but also in malignancy progression and chemoresistance. The ubiquitin-binding protein p62/Sqstm1 (p62), which is highly expressed in several cancers, competes with Nrf2 for Keap1 binding, leading to activation of Nrf2-mediated gene expression and survival of cancer cells. We had previously identified an inhibitor for the Keap1-phosphorylated-p62 (p-p62) protein-protein interaction (PPI), the acetonyl naphthalene derivative K67. In this study, we established facile synthetic routes for K67 and derivatives with various side chains on the C-2 position of naphthalene ring. K67 possessed high selectivity in the inhibition of Keap1-p-p62. Other derivatives showed potent Keap1-Nrf2 and Keap1-p-p62 PPI inhibitory activities, though the selectivity between the two activities was lower than K67.</p>

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研究発表 【 表示 ／ 非表示 】

  • フッ素導入により反応性代謝物の生成を回避した改良型Diclofenac類縁体の創製

    ○小川 真依、山田晶子、安田大輔、高橋恭子、中村成夫、大江知之、増野匡彦

    日本薬学会第139年会 (千葉) , 2019年03月, ポスター（一般）, 日本薬学会第139年会

  • ハード及びソフトな反応性代謝物を捕捉する新規蛍光標識トラッピング剤の創製

    ○柴崎智香子、髙橋恭子、中村成夫、大江知之、増野匡彦

    日本薬学会第139年会 (千葉) , 2019年03月, 口頭（一般）, 日本薬学会第139年会

  • オキシカム構造を模倣したスルホン類の抗パーキンソン病効果

    ○小町元輝、鈴木啓太、高橋恭子、中村成夫、大江知之、大久保知子、春名柚佳、田﨑嘉一、増野匡彦

    日本薬学会第139年会 (千葉) , 2019年03月, 口頭（一般）, 日本薬学会第139年会

  • ハードな反応性代謝物を捕捉する新規蛍光標識化トラッピング剤の創製

    ○長邑花、柴崎智香子、髙橋恭子、中村成夫、大江知之、増野匡彦

    日本薬学会第139年会 (千葉) , 2019年03月, ポスター（一般）, 日本薬学会第139年会

  • HIVプロテアーゼおよび逆転写酵素阻害活性を有する新規多標的型C60誘導体の創製：基質遷移状態模倣型イソスターとC60コアを結ぶリンカーの長さの検討

    ○古川 慶吾、髙橋恭子、中村成夫、大江知之、増野匡彦

    日本薬学会第139年会 (千葉) , 2019年03月, ポスター（一般）, 日本薬学会第139年会

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担当授業科目 【 表示 ／ 非表示 】

  • 課題研究（医薬品化学）

    2019年度

  • 演習（医薬品化学）

    2019年度

  • 卒業研究Ａ

    2019年度

  • 高度研究機器特別演習

    2019年度

  • 薬学英語演習Ａ

    2019年度

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