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Development of novel anti-tumor drugs targeting the stability of oncogenic fusion kinase proteins

Research Project

Project/Area Number 18K07311
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50020:Tumor diagnostics and therapeutics-related
Research InstitutionNational Institute of Health Sciences

Principal Investigator

Shibata Norihito  国立医薬品食品衛生研究所, 生化学部, 室長 (30391973)

Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords脱ユビキチン化酵素 / がん特異的融合タンパク質 / タンパク質分解 / がん / 融合キナーゼタンパク質
Outline of Final Research Achievements

Recently, fusion genes resulting from chromosomal rearrangements are found in a variety of tumor cells. Some of the products of such fusion genes are known to be driver oncogenic fusion proteins. In this study, we found that at least some of these oncogenic fusion proteins can be stably expressed in tumor cells by deubiquitylation. We also found that the deubiquitylating enzyme USP25 is involved in the stable expression of BCR-ABL, an oncogenic fusion kinase protein. In addition, it has been shown that deletion of USP25 expression or pharmacological inhibition of its activity leads to a decrease in BCR-ABL protein expression and suppression of the proliferation of BCR-ABL-positive cells. These results indicate that deubiquitylating enzyme would be a promising therapeutic target for the tumor caused by the oncogenic fusion proteins.

Academic Significance and Societal Importance of the Research Achievements

本研究により、脱ユビキチン化酵素ががん特異的融合タンパク質を安定化している可能性を提起した。これはがん細胞ではその増殖に必要なタンパク質を安定発現させる機構が存在していることを明らかにした点で学術的な意義が大きい。また脱ユビキチン化酵素ががん特異的融合タンパク質の創薬標的になり得ることを示したことから、標的タンパク質自体の酵素活性阻害ではなく分解を誘導する医薬品開発の可能性を提示することになり、他の様々な標的タンパク質に対する分子標的治療薬の開発にも適用できる波及効果の高い創薬コンセプトであると言える。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (21 results)

All 2022 2021 2020 2019 2018

All Journal Article (9 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 6 results,  Open Access: 3 results) Presentation (11 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Development of a degrader against oncogenic fusion protein FGFR3-TACC32022

    • Author(s)
      Shibata Norihito、Cho Nobuo、Koyama Hiroo、Naito Mikihiko
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 60 Pages: 128584-128584

    • DOI

      10.1016/j.bmcl.2022.128584

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Protocols for Synthesis of and the Methods to Evaluate the Anticancer Effects2021

    • Author(s)
      Tsukumo Yoshinori、Tsuji Genichiro、Yokoo Hidetomo、Shibata Norihito、Ohoka Nobumichi、Demizu Yosuke、Naito Mikihiko
    • Journal Title

      Methods Mol. Biol.

      Volume: 2365 Pages: 331-347

    • DOI

      10.1007/978-1-0716-1665-9_18

    • ISBN
      9781071616642, 9781071616659
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Discovery of a Highly Potent and Selective Degrader Targeting Hematopoietic Prostaglandin D Synthase via In Silico Design2021

    • Author(s)
      Yokoo Hidetomo、Shibata Norihito、Endo Akinori、Ito Takahito、Yanase Yuta、Murakami Yuki、Fujii Kiyonaga、Hamamura Kengo、Saeki Yasushi、Naito Mikihiko、Aritake Kosuke、Demizu Yosuke
    • Journal Title

      Journal of Medicinal Chemistry

      Volume: 64 Issue: 21 Pages: 15868-15882

    • DOI

      10.1021/acs.jmedchem.1c01206

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer2021

    • Author(s)
      Yokoo Hidetomo、Shibata Norihito、Naganuma Miyako、Murakami Yuki、Fujii Kiyonaga、Ito Takahito、Aritake Kosuke、Naito Mikihiko、Demizu Yosuke
    • Journal Title

      ACS Medicinal Chemistry Letters

      Volume: 12 Issue: 2 Pages: 236-241

    • DOI

      10.1021/acsmedchemlett.0c00605

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] 脱ユビキチン化酵素阻害によるプロテインノックダウン2020

    • Author(s)
      柴田識人, 内藤幹彦
    • Journal Title

      実験医学

      Volume: 38 Pages: 2337-2341

    • Related Report
      2020 Research-status Report
  • [Journal Article] がんに対する核酸医薬品の開発2020

    • Author(s)
      井上貴雄, 柴田識人
    • Journal Title

      がん分子標的治療

      Volume: 18 Pages: 78-86

    • Related Report
      2020 Research-status Report
  • [Journal Article] Deubiquitylase USP25 prevents degradation of BCR-ABL protein and ensures proliferation of Ph-positive leukemia cells2020

    • Author(s)
      Shibata Norihito、Ohoka Nobumichi、Tsuji Genichiro、Demizu Yosuke、Miyawaza Keiji、Ui-Tei Kumiko、Akiyama Tetsu、Naito Mikihiko
    • Journal Title

      Oncogene

      Volume: - Issue: 19 Pages: 3867-3878

    • DOI

      10.1038/s41388-020-1253-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a Potent Protein Degrader against Oncogenic BCR-ABL Protein2019

    • Author(s)
      Shibata Norihito、Ohoka Nobumichi、Hattori Takayuki、Naito Mikihiko
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 67 Issue: 3 Pages: 165-172

    • DOI

      10.1248/cpb.c18-00703

    • NAID

      130007606378

    • ISSN
      0009-2363, 1347-5223
    • Year and Date
      2019-03-01
    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 標的蛋白質分解を誘導するハイブリッド化合物SNIPERsとPROTACs.2018

    • Author(s)
      柴田識人, 内藤幹彦
    • Journal Title

      医学のあゆみ

      Volume: 267 Pages: 1069-1075

    • Related Report
      2018 Research-status Report
  • [Presentation] 造血器型プロスタグランジンD合成酵素選択的タンパク質分解誘導剤の開発2022

    • Author(s)
      柴田識人, 横尾英知, 遠藤彬則, 伊藤貴仁, 栁瀨雄太, 村上優貴, 藤井清永, 近藤一成, 佐伯泰, 内藤幹彦, 有竹浩介, 出水 庸介
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 造血器型プロスタグランジンD合成酵素を標的とした選択的タンパク質分解誘導剤の開発2021

    • Author(s)
      柴田識人, 横尾英知, 遠藤彬則, 伊藤貴仁, 栁瀨雄太, 村上優貴, 藤井清永, 近藤一成, 佐伯泰, 内藤幹彦, 有竹浩介, 出水 庸介
    • Organizer
      第94回日本生化学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 脱ユビキチン化によるがん特異的融合タンパク質の安定化2020

    • Author(s)
      柴田識人, 内藤幹彦
    • Organizer
      第79回 日本癌学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 発がん因子BCR-ABLの脱ユビキチン化は慢性骨髄性白血病細胞の増殖に必要である2020

    • Author(s)
      柴田識人, 大岡伸通, 辻厳一郎, 出水庸介, 内藤幹彦
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 発がん因子BCR-ABLの分解を誘導する2つのアプローチ2019

    • Author(s)
      柴田識人, 大岡伸通, 内藤幹彦
    • Organizer
      第19回 日本蛋白質科学会年会, 第71回 日本細胞生物学会大会 合同年次大会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 脱ユビキチン化による発がん因子BCR-ABLのタンパク質安定化2019

    • Author(s)
      柴田識人, 大岡伸通, 内藤幹彦
    • Organizer
      第92回 日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 脱ユビキチン化による発がん因子BCR-ABLの安定化は慢性骨髄性白血病細胞の増殖を促進する2019

    • Author(s)
      柴田識人, 大岡伸通, 内藤幹彦
    • Organizer
      第78回 日本癌学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 脱ユビキチン化によるがん特異的融合タンパク質の安定化2019

    • Author(s)
      柴田識人, 大岡伸通, 築茂由則, 内藤幹彦
    • Organizer
      新学術領域「ケモユビキチン」第三回班会議
    • Related Report
      2019 Research-status Report
  • [Presentation] A novel strategy for destabilization of oncogenic fusion protein BCR-ABL to inhibit growth of CML.2019

    • Author(s)
      Shibata N, Ohoka N, Naito M
    • Organizer
      5th International Symposium for Medicinal Sciences, 139th Annual Meeting of the Pharmaceutical Society of Japan
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 発がん因子BCR-ABLのタンパク質分解誘導剤とキナーゼ阻害剤の薬理学的相違2018

    • Author(s)
      柴田識人,大岡伸通,服部隆行,内藤幹彦
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 発がん因子BCR-ABLの蛋白質分解2018

    • Author(s)
      柴田 識人
    • Organizer
      第2回ユビキチン研究会
    • Related Report
      2018 Research-status Report
  • [Patent(Industrial Property Rights)] 新規化合物及び医薬組成物2020

    • Inventor(s)
      出水庸介, 柴田識人, 内藤幹彦, 有竹浩介, 横尾英知
    • Industrial Property Rights Holder
      出水庸介, 柴田識人, 内藤幹彦, 有竹浩介, 横尾英知
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-122534
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report

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Published: 2018-04-23   Modified: 2023-01-30  

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