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Screening of glutaminolysis or glutamine metabolism inhibitors

Research Project

Project/Area Number 19K05726
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
Research InstitutionMicrobial Chemistry Research Foundation

Principal Investigator

TAKEUCHI Toshifumi  公益財団法人微生物化学研究会, 微生物化学研究所, 研究員 (40516176)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsペプチド / エネルギー代謝 / 全合成 / 化学生物学 / 天然物 / 放線菌 / 阻害剤 / 作用機序解析 / 生理活性物質の探索 / 構造最適化
Outline of Research at the Start

がんは,様々な遺伝子変異の蓄積によって解糖系やグルタミン代謝などのエネルギー代謝経路を変化させて生存・増殖を有利にする.近年がん細胞の代謝経路の変化が,正常細胞との差別化が期待できる重要な開発領域として注目されている.例えば、殆どのがん細胞では解糖系が亢進されている (ワーバーグ効果).したがって,エネルギー代謝を阻害する化合物は,がん特有の代謝経路を利用した抗がん剤の候補として期待される.本研究ではエネルギー代謝阻害剤の設計・開発を目指す.その作用機序を解明し,抗腫瘍活性を評価する.

Outline of Final Research Achievements

In the metabolism modulator screening program, screening was performed using a glutamine compensation assay to target glutaminolysis, which measures the cytotoxicity of cells cultured in media with glutamine or dimethyl ketoglutarate. In the glutaminolysis pathway, glutamine enters the cell and is converted into glutamic acid and α-ketoglutarate (α-KG), which enters the TCA cycle. Thus, dimethyl ketoglutarate (DMKG), a pro-drug of α-KG, can compensate for glutamine. This study identified an active n-BuOH extract from Micromonospora sp. MM609M-173N6 with glutamine dependent cytotoxicity. An acyldipeptide micromonosporamide A was isolated by bioassay-guided fractionation. The compound exhibited glutamine-dependent antiproliferative activity against the A549 and HCT116 cell lines.

Academic Significance and Societal Importance of the Research Achievements

がんは様々な遺伝子変異の蓄積によって解糖系を亢進するなどエネルギー代謝経路を変化させて生存・増殖を有利にすることから,エネルギー代謝を阻害する化合物は,がん特有の代謝経路を利用した抗がん剤の候補として期待される.これまでの,エネルギー代謝阻害化合物の探索研究からアシルジペプチド マイクロモノスポラミドAを見出しその構造を決定するとともに合成経路を確立した.

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (10 results)

All 2022 2021 2019 Other

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (4 results) (of which Int'l Joint Research: 1 results) Remarks (2 results)

  • [Journal Article] Micromonosporamide A with Glutamine-Dependent Cytotoxicity from Micromonospora sp. MM609M-173N6: Isolation, Stereochemical Determination, and Synthesis2021

    • Author(s)
      Takeuchi Toshifumi、Hatano Masaki、Muramatsu Hideyuki、Kubota Yumiko、Sawa Ryuichi、Igarashi Masayuki
    • Journal Title

      Organic Letters

      Volume: 23 Issue: 20 Pages: 7981-7985

    • DOI

      10.1021/acs.orglett.1c02974

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Synthesis of nucleotide analogues, EFdA, EdA and EdAP, and the effect of EdAP on hepatitis B virus replication2019

    • Author(s)
      Kamata Mai、Takeuchi Toshifumi、Hayashi Ei、Nishioka Kazane、Oshima Mizuki、Iwamoto Masashi、Nishiuchi Kota、Kamo Shogo、Tomoshige Shusuke、Watashi Koichi、Kamisuki Shinji、Ohrui Hiroshi、Sugawara Fumio、Kuramochi Kouji
    • Journal Title

      Bioscience, Biotechnology, and Biochemistry

      Volume: 84 Issue: 2 Pages: 217-227

    • DOI

      10.1080/09168451.2019.1673696

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Design, Synthesis, and Biological Evaluation of EdAP, a 4′-Ethynyl-2′-Deoxyadenosine 5′-Monophosphate Analog, as a Potent Influenza a Inhibitor2019

    • Author(s)
      Takeuchi Toshifumi、Sriwilaijaroen Nongluk、Sakuraba Ayako、Hayashi Ei、Kamisuki Shinji、Suzuki Yasuo、Ohrui Hiroshi、Sugawara Fumio
    • Journal Title

      Molecules

      Volume: 24 Issue: 14 Pages: 2603-2603

    • DOI

      10.3390/molecules24142603

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pyrenocine A induces monopolar spindle formation and suppresses proliferation of cancer cells2019

    • Author(s)
      Myobatake Yusuke、Kamisuki Shinji、Tsukuda Senko、Higashi Tsunehito、Chinen Takumi、Takemoto Kenji、Hachisuka Masami、Suzuki Yuka、Takei Maya、Tsurukawa Yukine、Maekawa Hiroaki、Takeuchi Toshifumi、Matsunaga Tomoko M.、Sahara Hiroeki、Usui Takeo、Matsunaga Sachihiro、Sugawara Fumio
    • Journal Title

      Bioorganic & Medicinal Chemistry

      Volume: 27 Issue: 23 Pages: 115149-115149

    • DOI

      10.1016/j.bmc.2019.115149

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] グルタミン依存的な細胞増殖抑制活性を示すマイクロモノスポラミドA: 単離・構造決定及び合成2022

    • Author(s)
      竹内 倫文,村松 秀行,波多野 和樹,久保田 由美子,澤 竜一,五十嵐 雅之
    • Organizer
      第39回メディシナルケミストリーシンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] グルタミン依存的な細胞増殖抑制活性を示すマイクロモノスポラミドAの単離・構造決定及び合成2022

    • Author(s)
      竹内 倫文、村松 秀行、波多野 和樹、久保田 由美子、澤 竜一、五十嵐 雅之
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Research-status Report
  • [Presentation] ATP枯渇活性を有する36員環ポリオール系マクロライド deplelide A及びBの単離・同定2019

    • Author(s)
      竹内倫文,波多野和樹,梅北まや,林千草,和田俊一,永吉美穂,澤竜一,久保田由美子,川田学,五十嵐雅之,柴崎正勝
    • Organizer
      第7回がんと代謝研究会in仙台
    • Related Report
      2019 Research-status Report
  • [Presentation] Screening of Cancer Metabolism Inhibitor2019

    • Author(s)
      Toshifumi Takeuchi
    • Organizer
      The Joint Symposium of "10th Korea-Japan Chemical Biology Symposium" and "30th Meeting for New Drug Discovery" in Kanazawa
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Remarks] 微生物化学研究所

    • URL

      https://www.bikaken.or.jp/

    • Related Report
      2022 Annual Research Report 2020 Research-status Report 2019 Research-status Report
  • [Remarks] IMC 微生物化学研究所

    • URL

      https://www.bikaken.or.jp/

    • Related Report
      2021 Research-status Report

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Published: 2019-04-18   Modified: 2024-01-30  

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