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Development of molecular-targeting prodrug for ENPP1

Research Project

Project/Area Number 18K14358
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 37030:Chemical biology-related
Research InstitutionNagoya City University

Principal Investigator

Kawaguchi Mitsuyasu  名古屋市立大学, 医薬学総合研究院(薬学), 講師 (10735682)

Project Period (FY) 2018-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywordsプロドラッグ / ENPP1 / がん幹細胞
Outline of Final Research Achievements

Becuase I found that ENPP1 specifically recognizes and hydrolyzes mGMP groups in living cells, I tried to apply mGMP group to the approved anticancer drug and aimed to develop a compound that shows cytotoxicity in ENPP1 overexpressing cells. However, when we attempted to prodrug SN-38, it was found that the mGMP group was unstable on the synthesis. Considering the background of previous studies, the acidity of the prodrug group is considered to be a key factor in the synthesis of the prodrug. In the result of an investigation of reaction conditions, it was found that coumarin, which is less acidic than TG, is also possible to synthesize Cou-mGMP. By using this reaction condition, I think that I can synthesize various prodrug compounds having mGMP group.

Academic Significance and Societal Importance of the Research Achievements

本研究ではENPP1 (ecto-nucleotide pyrophosphatase/ phosphodiesterase 1)という細胞外に触媒ドメインを持つ膜タンパク質に着目し、その酵素活性を利用したプロドラッグ技術の開発を目指す。ENPP1は悪性度の高い脳腫瘍や乳がんで発現量が著しく高いことが示され 、がん幹細胞性の獲得・維持に必要であることが報告されているため、ENPP1を標的とすることは「がん幹細胞を標的」とすることとなり、神経膠芽腫やトリプルネガティブ乳がんなど悪性度が高く、有効な治療法の乏しいがんに対して効果的かつ副作用の少ない治療法を提案できると考えられる。

Report

(3 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • Research Products

    (22 results)

All 2020 2019 2018

All Journal Article (13 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 13 results,  Open Access: 6 results) Presentation (4 results) Book (1 results) Patent(Industrial Property Rights) (4 results) (of which Overseas: 1 results)

  • [Journal Article] Identification of Potent in Vivo Autotaxin Inhibitors that Bind to Both Hydrophobic Pockets and Channels in the Catalytic Domain2020

    • Author(s)
      Kawaguchi Mitsuyasu、Okabe Takayoshi、Okudaira Shinichi、Hama Kotaro、Kano Kuniyuki、Nishimasu Hiroshi、Nakagawa Hidehiko、Ishitani Ryuichiro、Kojima Hirotatsu、Nureki Osamu、Aoki Junken、Nagano Tetsuo
    • Journal Title

      Journal of Medicinal Chemistry

      Volume: 63 Issue: 6 Pages: 3188

    • DOI

      10.1021/acs.jmedchem.9b01967

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multiplexed single-molecule enzyme activity analysis for counting disease-related proteins in biological samples2020

    • Author(s)
      Shingo Sakamoto, Toru Komatsu, Rikiya Watanabe, Yi Zhang, Taiki Inoue, Mitsuyasu Kawaguchi, Hidehiko Nakagawa, Takaaki Ueno, Takuji Okusaka, Kazufumi Honda, Hiroyuki Noji, Yasuteru Urano
    • Journal Title

      Science Advances

      Volume: 6 Issue: 11

    • DOI

      10.1126/sciadv.aay0888

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a Novel Intraocular-Pressure-Lowering Therapy Targeting ATX2019

    • Author(s)
      Nagano Norimichi、Honjo Megumi、Kawaguchi Mitsuyasu、Nishimasu Hiroshi、Nureki Osamu、Kano Kuniyuki、Aoki Junken、Komatsu Toru、Okabe Takayoshi、Kojima Hirotatsu、Nagano Tetsuo、Aihara Makoto
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 11 Pages: 1926-1935

    • DOI

      10.1248/bpb.b19-00567

    • NAID

      130007740593

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-11-01
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] <i>In Cellullo</i> and <i>ex Vivo</i> Availability of a Yellowish-Green-Light-Controllable NO Releaser2019

    • Author(s)
      Naoya Ieda, Yuji Hotta, Mitsuyasu Kawaguchi, Kazunori Kimura, and Hidehiko Nakagawa
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 67 Issue: 6 Pages: 576-579

    • DOI

      10.1248/cpb.c19-00112

    • NAID

      130007657414

    • ISSN
      0009-2363, 1347-5223
    • Year and Date
      2019-06-01
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Life-oriented Chemistry in Pharmaceutical Sciences2019

    • Author(s)
      Kawaguchi M, Taniguchi A.
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 139 Issue: 2 Pages: 261-262

    • DOI

      10.1248/yakushi.18-00174-F

    • NAID

      130007599887

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2019-02-01
    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Development of a highly sensitive fluorescence probe for peptidyl arginine deiminase (PAD) activity2019

    • Author(s)
      Kunieda Kazuki、Kawaguchi Mitsuyasu、Ieda Naoya、Nakagawa Hidehiko
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 29 Issue: 7 Pages: 923-928

    • DOI

      10.1016/j.bmcl.2019.01.032

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of Peptide-Based Sirtuin Defatty-Acylase Inhibitors Identified by the Fluorescence Probe, SFP3, That Can Efficiently Measure Defatty-Acylase Activity of Sirtuin2019

    • Author(s)
      Mitsuyasu Kawaguchi, Naoya Ieda, and Hidehiko Nakagawa
    • Journal Title

      J. Med. Chem.

      Volume: 62 Issue: 11 Pages: 5434-5452

    • DOI

      10.1021/acs.jmedchem.9b00315

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of an ENPP1 Fluorescence Probe for Inhibitor Screening, Cellular Imaging, and Prognostic Assessment of Malignant Breast Cancer2019

    • Author(s)
      Kawaguchi Mitsuyasu、Han Xiang、Hisada Tomoka、Nishikawa Sayaka、Kano Kuniyuki、Ieda Naoya、Aoki Junken、Toyama Tatsuya、Nakagawa Hidehiko
    • Journal Title

      Journal of Medicinal Chemistry

      Volume: 62 Issue: 20 Pages: 9254-9269

    • DOI

      10.1021/acs.jmedchem.9b01213

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ratiometric assay of CARM1 activity using a FRET-based fluorescent probe2019

    • Author(s)
      Ohta Yuhei、Wakita Hiroo、Kawaguchi Mitsuyasu、Ieda Naoya、Osada Shigehiro、Nakagawa Hidehiko
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 29 Issue: 22 Pages: 126728-126728

    • DOI

      10.1016/j.bmcl.2019.126728

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structure-efficiency relationship of photoinduced electron transfer-triggered nitric oxide releasers.2019

    • Author(s)
      Ieda N, Oka Y, Yoshihara T, Tobita S, Sasamori T, Kawaguchi M, Nakagawa H
    • Journal Title

      Sci Rep

      Volume: 9 Issue: 1 Pages: 1430-1430

    • DOI

      10.1038/s41598-018-38252-5

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] PlexinD1 signaling controls morphological changes and migration termination in newborn neurons2018

    • Author(s)
      Sawada Masato、Ohno Nobuhiko、Kawaguchi Mitsuyasu、Huang Shih‐hui、Hikita Takao、Sakurai Youmei、Bang Nguyen Huy、Quynh Thai Truc、Ishido Yuri、Yoshida Yutaka、Nakagawa Hidehiko、Uemura Akiyoshi、Sawamoto Kazunobu
    • Journal Title

      The EMBO Journal

      Volume: 37 Issue: 4

    • DOI

      10.15252/embj.201797404

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Development of a fluorescent probe for detection of citrulline based on photo-induced electron transfer2018

    • Author(s)
      Kunieda Kazuki、Yamauchi Hiromasa、Kawaguchi Mitsuyasu、Ieda Naoya、Nakagawa Hidehiko
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 28 Issue: 5 Pages: 969-973

    • DOI

      10.1016/j.bmcl.2018.01.026

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Development and cellular application of visible-light-controllable HNO releasers based on caged Piloty's acid.2018

    • Author(s)
      Kawaguchi M, Tani T, Hombu R, Ieda N, Nakagawa H
    • Journal Title

      Chem Commun

      Volume: 54 Issue: 73 Pages: 10371-10374

    • DOI

      10.1039/c8cc04954h

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Presentation] caspase-1活性を指標とした単一細胞パイロトーシス可視化プローブの開発2018

    • Author(s)
      川口充康、山田輝、家田直弥、中川秀彦
    • Organizer
      平成30年度生理学研究所研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] Dinitrobenzene骨格を有するCys-SSH検出蛍光プローブの開発と細胞での機能評価2018

    • Author(s)
      川口充康、若森久幸、家田直弥、中川秀彦
    • Organizer
      第71回日本酸化ストレス学会学術集会・第18回日本NO学会合同学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Dinitrobenzene骨格を基盤としたCys-SSH蛍光プローブ類の開発と生細胞での機能評価2018

    • Author(s)
      川口充康、若森久幸、家田直弥、中川秀彦
    • Organizer
      日本ケミカルバイオロジー学会第13回年会
    • Related Report
      2018 Research-status Report
  • [Presentation] SIRT2脱アシル化活性阻害剤の開発2018

    • Author(s)
      川口充康、家田直弥、中川秀彦
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Research-status Report
  • [Book] Precision Medicine2019

    • Author(s)
      川口充康、中川秀彦
    • Total Pages
      6
    • Publisher
      北隆館
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 化合物、光応答性放出制御剤2019

    • Inventor(s)
      家田直弥、中川秀彦、川口充康
    • Industrial Property Rights Holder
      家田直弥、中川秀彦、川口充康
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] ナノ粒子、水性分散液、一酸化窒素放出制御剤2019

    • Inventor(s)
      家田直弥、中川秀彦、川口充康
    • Industrial Property Rights Holder
      家田直弥、中川秀彦、川口充康
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] マイクロデバイスを用いたENPP活性検出法の開発2019

    • Inventor(s)
      浦野泰照、小松徹、坂本眞伍、野地博行、中川秀彦、川口充康、他
    • Industrial Property Rights Holder
      浦野泰照、小松徹、坂本眞伍、野地博行、中川秀彦、川口充康、他
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 化合物、光応答性酸素消費剤2019

    • Inventor(s)
      家田直弥、中川秀彦、川口充康
    • Industrial Property Rights Holder
      家田直弥、中川秀彦、川口充康
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report

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Published: 2018-04-23   Modified: 2021-02-19  

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