OHE Tomoyuki

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmaceutical Sciences 医薬品化学講座 (Shiba-Kyoritsu)

Position

Associate Professor

E-mail Address

E-mail address

External Links

Career 【 Display / hide

  • 1996.04
    -
    1997.03

    日本学術振興会 特別研究員

  • 1997
    -
    1999

    万有製薬株式会社(MSD) つくば研究所 創薬研究所

  • 1999
    -
    2000

    Merck Research Laboratories(West Point, PA, USA)

  • 2000
    -
    2009

    万有製薬株式会社(MSD) つくば研究所 薬物動態研究所

  • 2009
    -
    2011

    大鵬薬品工業株式会社 創薬センター 分子標的薬研究所

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Academic Background 【 Display / hide

  • 1992.03

    The University of Tokyo, Faculty of Pharmaceutical Science, 製薬化学科

    University, Graduated

  • 1994.03

    The University of Tokyo, Graduate School, Division of Pharmaceutical Sciences, 生命薬学

    Graduate School, Completed, Master's course

  • 1997.03

    The University of Tokyo, Graduate School, Division of Pharmaceutical Sciences, 生命薬学

    Graduate School, Completed, Doctoral course

Academic Degrees 【 Display / hide

  • PhD, The University of Tokyo, Coursework, 1997.03

Licenses and Qualifications 【 Display / hide

  • 薬剤師, 1992

 

Research Areas 【 Display / hide

  • Chemical pharmacy (Chemical Pharmaceutical Science)

  • Physical pharmacy

  • Drug development chemistry (Drug Development Chemistry)

Research Keywords 【 Display / hide

  • 創薬化学

  • drug metabolism

  • 分析化学

  • pharmacokinetics

  • antioxidant

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Research Themes 【 Display / hide

  • Strategic Drug Design to Eliminate Metabolic Activation of Hapatotoxic Drugs, 

    2011
    -
    Present

  • Lead optimization considering drug metabolism, 

    2012
    -
    Present

  • 反応性代謝物を捕捉する新規トラッピング剤の開発, 

    2017
    -
    Present

  • 臓器標的型プロドラッグ戦略の開発, 

    2018
    -
    Present

  • Synthesis of fullerene derivatives and their biological activities, 

    2011
    -
    Present

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Books 【 Display / hide

  • フラーレン誘導体・内包技術の最前線.

    Ohe T, Mashino T., シーエムシー出版, 東京, 2014.04

    Scope: 237-247

  • 創薬研究のストラテジー.

    岩尾洋, 飯野正光, 赤池昭紀監修., 金芳堂, 日本, 2012.02

    Scope: 232-239

Papers 【 Display / hide

  • Synthesis and antitumor activity of novel pyridinium fullerene derivatives

    Takumi Yasuno, Tomoyuki Ohe, Hitomi Ikeda, Kyoko Takahashi, Shigeo Nakamura, Tadahiko Mashino

    International Journal of Nanomedicine (International Journal of Nanomedicine)  14   6325 - 6337 2019.08

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  11769114

     View Summary

    © 2019 Yasuno et al. Purpose: We have previously reported that some cationic fullerene derivatives exhibited anticancer activity, and they are expected to be a potential lead compound for an anti-drug resistant cancer agent. However, they are bis-adducts and a mixture of multiple regioisomers, which cannot be readily separated due to the variability of substituent positions on the fullerene cage. To overcome this issue, we evaluated the antiproliferative activities of a set of mono-adduct derivatives and examined their structure-activity relationship. In addition, the in vivo antitumor activity of selected derivatives was also examined. Methods: Nineteen pyridinium fullerene derivatives were newly designed and synthesized in this study. Their antiproliferative activities were evaluated using several cancer cell lines including drug-resistant cells. Furthermore, in vivo antitumor activity of several derivatives was investigated in mouse xenograft model of human lung cancer. Results: The derivatives inhibited the proliferation of cancer cell lines, including cisplatin-resistant cells and doxorubicin-resistant cells. It was also shown that compound 10 (10 μM), 13 (10 μM) and cis-14 (10 μM) induced the intracellular oxidative stress. In addition, compound 13 (20 mg/kg) and cis-14 (15 mg/kg) significantly exhibited antitumor activity in mouse xenograft model of human lung cancer. Conclusion: We synthesized a novel set of mono-adduct fullerene derivatives functionalized with pyridinium groups and found that most of them show potent antiproliferative activities against cancer cell lines and some of them show significant antitumor activities in vivo. We propose that these fullerene derivatives serve as the lead compounds for a novel type of antitumor agents.

  • N-Acetyl cysteine prevents activities of STAT3 inhibitors, Stattic and BP-1-102 independently of its antioxidant properties

    Yuki Uchihara, Tomoyuki Ohe, Tadahiko Mashino, Takayuki Kidokoro, Hiroomi Tamura and Megumi Funakoshi-Tago

    Pharmacological Reports (Pharmacological Reports)  71 ( 6 ) 1067 - 1078 2019.05

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  17341140

     View Summary

    © 2019 Institute of Pharmacology, Polish Academy of Sciences Background: Inhibitors for signal transducer and activator of transcription 3 (STAT3), Stattic, BP-1-102, and LLL12 significantly induce apoptosis in transformed Ba/F3 cells expressing an oncogenic fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) that induces the activation of STAT3. We found that the antioxidant reagent, N-acetyl cysteine (NAC) prevented the abilities of Stattic and BP-1-102, but not LLL12 to induce apoptosis in transformed cells expressing NPM-ALK, providing a novel problem in use of STAT3 inhibitors. We herein investigated the mechanisms how NAC prevented the effects of Sttatic and BP-1-102. Methods: Ba/F3 cells expressing NPM-ALK and SUDHL-1 cells were treated with antioxidants such as NAC, Trolox or edaravone in combination with STAT3 inhibitors. Phosphorylation of STAT3, cell proliferation rate, cell viability, cell cycle, internucleosomal DNA fragmentation and the intracellular accumulation of reactive oxygen species (ROS) was investigated. The binding of STAT3 inhibitors and NAC was analyzed by LC–MS. Results: NAC but not Trolox and edaravone diminished the abilities of Stattic and BP-1-102 to induce apoptosis in cells expressing NPM-ALK. The ROS levels in cells expressing NPM-ALK were not markedly affected by the treatments with Stattic and BP-1-102 in combination with NAC, suggesting that NAC inhibited the activity of Stattic and BP-1-102 independent of its antioxidant activity. LC–MS analysis revealed that NAC directly bound to Stattic and BP-1-102. Furthermore, these NAC adducts exhibited no cytotoxicity, and failed to affect the activity of STAT3. Conclusions: NAC antagonizes the activities of Stattic and BP-1-102, which inhibit STAT3 activation by interacting with cysteine residues in STAT3.

  • Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation

    Ohe T, Umezawa R, Kitagawara Y, Yasuda D, Takahashi K, Nakamura S, Abe A, Sekine S, Ito K, Okunushi K, Morio H, Furihata T, Anzai N, Mashino T.

    Bioorg Med Chem Lett (Bioorganic and Medicinal Chemistry Letters)  28 ( 23-24 ) 3708 - 3711 2018.12

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0960894X

     View Summary

    © 2018 Elsevier Ltd We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR.

  • Hit-to-lead in academia: Discovery of a protein-protein interaction inhibitor of Keap1-Nrf2

    Yasuda D., Obata R., Takahashi K., Ohe T., Mashino T.

    Yakugaku Zasshi (Yakugaku Zasshi)  138 ( 8 ) 1059 - 1065 2018

    ISSN  00316903

     View Summary

    © 2018 The Pharmaceutical Society of Japan. 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.

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

    Yasuda, D., Yuasa, A., Obata, R., Nakajima M., Takahashi, K., Ohe, T., Ichimura, Y., Komatsu, M., Yamamoto, M., Imamura, R., Kojima, H., Okabe, T., Nagano, T., and Mashino, T.

    Bioorg Med Chem Lett 27 ( 22 ) 5006 - 5009 2017.11

    Research paper (scientific journal), Joint Work, Accepted

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

  • Drug discovery of safer drugs by eliminating metabolic activation of existing drugs

    大江知之

    Precision Medicine (北隆館)  2 ( 9 ) 47 - 51 2019.08

    Introduction and explanation (scientific journal), Single Work

  • Hit-to-Lead in Academia: Discovery of a Protein-Protein Interaction Inhibitor of Keap1-Nrf2

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

    YAKUGAKU ZASSHI 138 ( 8 ) 1059 - 1065 2018.08

    Introduction and explanation (scientific journal), Joint Work

  • ヒトや野生生物における医薬品、環境化学物質の安全性評価の精度向上にむけて -代謝的活性化、種差、エピジェネティクスの観点から 肝毒性を示す医薬品の代謝活性化機構の解析とそれに基づいた創薬戦略

    大江知之, 高橋恭子, 中村成夫, 増野匡彦

    薬学雑誌 137 ( 3 ) 249 - 255 2017.03

    Introduction and explanation (scientific journal), Joint Work

  • 反応性代謝物とその評価.

    Ohe T.

    日本薬理学雑誌 (日本薬理学会)  134   338-341 2009.12

    Introduction and explanation (scientific journal), Single Work

  • Evaluation of drug interactions with P-glycoprotein in drug discovery: in vitro assessment of the potential for drug-drug interactions with P-glycoprotein.

    Hochman JH, Yamazaki M, Ohe T, Lin JH.

    Curr Drug Metab (Bentham Science Publishers)  3   257-273 2002.06

    Introduction and explanation (scientific journal), Joint Work

Presentations 【 Display / hide

  • Synthesis and biological evaluation of novel nevirapine analogs designed to avoid metabolic activation

    Yasuhiro Tateishi, Tomoyuki Ohe, Kyoko Takahashi, Shigeo Nakamura, Tadahiko Mashino

    2018 International Meeting on 22nd MDO and 33rd JSSX, 2018.10, Poster (general)

  • がん細胞増殖抑制効果を有するカチオン型フラーレン誘導体による活性酸素産生およびその構造活性相関

    池田 瞳、安田 大輔、高橋 恭子、中村 成夫、大江 知之、増野 匡彦

    第62回日本薬学会関東支部大会 (東京) , 2018.09, Oral Presentation(general)

  • 新規アザフレロイド誘導体の合成と HCV RNA ポリメラーゼ阻害活性

    薮内大貴、片岡裕樹、高橋 恭子、中村 成夫、大江 知之、増野 匡彦

    第62回日本薬学会関東支部大会 (東京) , 2018.09, Oral Presentation(general)

  • Synthesis of a fluoroalkene mimic of an amide drug via copper-catalyzed defluoroborylation and evaluation of its properties

    Takashi Niwa, Yuta Uetake, Motoyuki Isoda, Tomoyuki Ohe, Daisuke Yasuda, Tadahiko Mashino, Takamitsu Hosoya

    The 13th Annual Meeting of Japanese Society for Chemical Biology, 2018.06, Poster (general)

  • 抗がん剤耐性克服を志向したKeap1-リン酸化p62タンパク質間相互作用阻害剤の創薬研究

    安田大輔、中島真央、大江知之、高橋恭子、小松雅明、一村義信、山本雅之、 今村理世、小島宏建、岡部隆義、長野哲雄、増野匡彦

    第71回日本酸化ストレス学会 (京都) , 2018.05, Poster (general)

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • 既存薬のADMET 特性を変換することによる新規医薬品の創製研究

    2019.04
    -
    2020.03

    慶應義塾, 福澤基金研究補助, 大江知之, Research grant, Principal Investigator

  • 次世代測定技術を用いた生体内オートファジー動態解析

    2018.04
    -
    2021.03

    Grant-in-Aid for Scientific Research, 小松 雅明, Research grant, Co-investigator

  • 成功確率の高いリード創出を支援する高機能ADMET評価基盤の構築

    2017.04
    -
    2022.03

    日本医療研究開発機構, 創薬等ライフサイエンス研究支援基盤事業, 増野匡彦, Research grant, Co-investigator

  • 神経細胞死保護作用を有するテトラロン型新規パーキンソン病治療薬の創製

    2017.04
    -
    2019.03

    AMED, 橋渡し研究戦略的推進プログラム シーズ A, 増野匡彦, Co-investigator

  • 肝障害を有する医薬品の代謝活性化機構の解明とそれを基盤にした低毒性医薬品の創製

    2016.04
    -
    2020.03

    公益財団法人篷庵社, 研究助成, 大江知之, Research grant, Principal Investigator

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Intellectual Property Rights, etc. 【 Display / hide

  • パーキンソン病治療薬

    Application No.: 特願2019-014281  2019.01 

    Patent, Joint, National application

  • 潰瘍性大腸炎の予防または治療剤と新規フラーレン誘導体

    Application No.: PCT/JP2014/053950  2014.02 

    Announcement No.: WO2014/129513  2014.08 

    Patent, Joint, PCT international application

  • 潰瘍性大腸炎の予防または治療剤と新規フラーレン誘導体

    Application No.: 特願2013-030455  2013.02 

    Patent, Joint

 

Courses Taught 【 Display / hide

  • STUDY OF MAJOR FIELD: (BIOORGANIC AND MEDICINAL CHEMISTRY)

    2019

  • SEMINAR: (BIOORGANIC AND MEDICINAL CHEMISTRY)

    2019

  • RESEARCH FOR BACHELOR'S THESIS A

    2019

  • RESEARCH APPARATUS LABORATORY COURSE

    2019

  • PHARMACEUTICAL-ENGLISH SEMINAR A

    2019

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Courses Previously Taught 【 Display / hide

  • C4(4)化学物質の構造決定

    Keio University, 2015, Autumn Semester, Major subject, Lecture, Within own faculty, 200people

  • C5(1)官能基の導入・変換

    Keio University, 2015, Spring Semester, Major subject, Lecture, Within own faculty, 200people

  • C5(2)複雑な化合物の合成

    Keio University, 2015, Autumn Semester, Major subject, Lecture, Within own faculty, 200people

  • C6(1)生体分子のコアとパーツB

    Keio University, 2015, Spring Semester, Major subject, Lecture, Within own faculty, 200people

  • 精密有機合成

    Keio University, 2015, Autumn Semester, Major subject, Lecture, Within own faculty, 60people

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Educational Activities and Special Notes 【 Display / hide

  • スタンダード薬学シリーズⅡ 化学系薬学 Ⅱ生体分子・医薬品の化学による理解 日本薬学会編 東京化学同人 

    2016.04

    , Development of Textbook and Teaching Material

 

Social Activities 【 Display / hide

  • 日本薬学会代議員

    2019.03
    -
    2021.03
  • 日本薬物動態学会評議員

    2014.04
    -
    Present

Memberships in Academic Societies 【 Display / hide

  • 日本分析化学会, 

    2016
    -
    Present
  • 日本酸化ストレス学会, 

    2012
    -
    Present
  • 日本薬物動態学会, 

    2008
    -
    Present
  • 日本薬学会(医薬化学部会), 

    1992
    -
    Present

Committee Experiences 【 Display / hide

  • 2013.10
    -
    2015.09

    学生交換・在外研修委員, 慶應義塾国際センター

  • 2013.10
    -
    2015.09

    学習指導主任, 慶應義塾国際センター

  • 2017.04
    -
    Present

    学生相談室芝共立キャンパス兼担カウンセラー, 慶應義塾

  • 2017.10
    -
    Present

    芝共立キャンパスITC所長, 慶應義塾

  • 2014.04
    -
    Present

    CBT実施委員長, 慶應義塾大学薬学部