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 Evaluation of Nevirapine Analogs to Study the Metabolic Activation of Nevirapine

    Yasuhiro Tateishi, Tomoyuki Ohe, Daisuke Yasuda, Kyoko Takahashi, Shigeo Nakamura, Yasuhiro Kazuki, Tadahiko Mashino

    Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics)  35 ( 2 ) 238 - 243 2020.04

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  13474367

     View Summary

    Nevirapine (NVP) is widely used as a non-nucleoside reverse transcriptase inhibitor of HIV-1, however, it is associated with severe skin and liver injury. The mechanisms of these adverse reactions are not yet clear, but the metabolic activation of NVP is thought to be related to the injury process. Until now, several metabolic activation pathways of NVP have been reported. In this study, in order to identify the reactive metabolite of NVP mainly responsible for CYP inhibition and liver injury, we synthesized five NVP analogs designed to avoid the proposed bioactivation pathway and evaluated their metabolic stabilities, CYP3A4 time-dependent inhibitory activities, and cytotoxicity. As a result, only a pyrimidine analog of NVP, which could avoid the formation of a reactive epoxide intermediate, did not inhibit CYP3A4. Outside of this compound, the other synthesized compounds, which could avoid the generation of a reactive quinone-methide intermediate, inhibited CYP3A4 equal to or stronger than NVP. The pyrimidine analog of NVP did not induce cytotoxicity in HepG2 and transchromosomic HepG2 cells, expressing major four CYP enzymes and CYP oxidoreductase. These results indicated that the epoxide intermediate of NVP might play an important role in NVP-induced liver injury.

  • Inhibitors of the protein–protein interaction between phosphorylated p62 and Keap1 attenuate chemoresistance in a human hepatocellular carcinoma cell line

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

    Free Radical Research  2020.03

    Research paper (scientific journal), Accepted,  ISSN  10715762

     View Summary

    © 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group. Resistance to anticancer agents has been an obstacle to developing therapeutics and reducing medical costs. Whereas sorafenib is used for the treatment of human hepatocellular carcinoma (HCC), resistance limits its efficacy. p62, a multifunctional protein, is overexpressed in several HCC cell lines, such as Huh-1 cells. Phosphorylated p62 (p-p62) inhibits the protein–protein interaction (PPI) between Keap1 and Nrf2, resulting in the Nrf2 overactivation that causes drug resistance. We have found a unique Nrf2 inactivator, named K67, that inhibited the PPI between Keap1 and p-p62 and attenuated sorafenib resistance in Huh-1 cells. Herein, we designed and synthesised novel K67 derivatives by modification of the substituent at the 4-position of the two benzenesulfonyl groups of K67. Although these new derivatives inhibited the Keap1-p-p62 PPI to a level comparable to or weaker than that of K67, the isopropoxy derivative enhanced the sensitivity of Huh-1 cells to sorafenib to a greater extent than K67 without any influence on the viability of Huh-7 cells, which is a non-resistant HCC cell line. The isopropoxy derivative also increased the sensitivity of Huh-1 cells to regorafenib, which suggests that this derivative has the potential to be used as an agent to overcome chemoresistance based on Nrf2 inactivation.

  • 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 14   6325 - 6337 2019.08

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

     View Summary

    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 71 ( 6 ) 1067 - 1078 2019.05

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

     View Summary

    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.

    Bioorganic and Medicinal Chemistry Letters 28 ( 23-24 ) 3708 - 3711 2018.10

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

     View Summary

    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.

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

Reviews, Commentaries, etc. 【 Display / hide

  • Drug discovery of safer benzbromarone derivatives

    Tomoyuki Ohe

    BIO Clinica (北隆館)  35 ( 2 ) 59 - 62 2020.02

    Introduction and explanation (scientific journal)

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

    Tomoyuki Ohe

    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

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Presentations 【 Display / hide

  • 代謝活性化回避を指向した新規ジクロフェナク類縁体の合成と評価

    立石泰寛, 大江知之, 小川真依, 安田大輔, 高橋恭子, 中村成夫, 増野匡彦

    日本薬学会第140 年会 (京都) , 2020.03, Oral Presentation(general)

  • HIV/HCV共感染治療薬を志向した 多標的型ピリジニウム型C60誘導体の創製

    小林透威, 高橋恭子, 中村成夫, 大江知之, 増野匡彦

    日本薬学会第140年会 (京都) , 2020.03, Oral Presentation(general)

  • Wntシグナル抑制によりウイルス感染非ホジキンリンパ腫の細胞増殖を抑制するフラーレン誘導体の開発

    門田彩乃,森口美里,渡部匡史,中村成夫,安野拓実,大江知之,増野匡彦,藤室雅弘

    日本薬学会第140年会 (京都) , 2020.03, Poster (general)

  • トラッピング剤を用いた反応性アシルグルクロニドの新規検出法

    柴﨑 智香子, 高橋 恭子, 中村成夫, 大江 知之, 増野 匡彦

    日本薬学会第140年会 (京都) , 2020.03, Oral Presentation(general)

  • Synthesis and evaluation of novel diclofenac analogues to mitigate its metabolic activation via glucuronidation

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

    日本薬物動態学会第34回年会 (つくば) , 2019.12, Oral Presentation(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.: PCT/JP2020/003462  2020.01 

    Patent, Joint, PCT international application

  • 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

Awards 【 Display / hide

  • 2019年度学部長賞(教育)

    2020.03, 慶應義塾大学薬学部

    Type of Award: Keio commendation etc.

  • 2017年度学部長賞(運営)

    2018.03, 慶應義塾大学薬学部

    Type of Award: Keio commendation etc.

  • Merck Award for Excellence

    2008.07

  • Drug Metabolism of Disposition Best Paper of the Year 1997

    1997

 

Courses Taught 【 Display / hide

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

    2020

  • SEMINAR: (BIOORGANIC AND MEDICINAL CHEMISTRY)

    2020

  • RESEARCH FOR BACHELOR'S THESIS 1

    2020

  • RESEARCH APPARATUS LABORATORY COURSE

    2020

  • PHARMACEUTICAL-ENGLISH SEMINAR

    2020

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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