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Protein Knockdown Approach : Hybrid Small Molecules which Induce Proteasome Degradation of Target Proteins

Research Project

Project/Area Number 21651092
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeSingle-year Grants
Research Field Living organism molecular science
Research InstitutionThe University of Tokyo

Principal Investigator

HASHIMOTO Yuichi  東京大学, 分子細胞生物学研究所, 教授 (90164798)

Co-Investigator(Renkei-kenkyūsha) ISHIKAWA Minoru  東京大学, 分子細胞生物学研究所, 助教 (70526839)
Project Period (FY) 2009 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥3,170,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥270,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2009: ¥700,000 (Direct Cost: ¥700,000)
Keywords生物活性分子の設計・合成 / タンパク質の自己分解 / ベスタチン / ユビキチン / タンパク質分解誘導 / cIAP1 / プロテアソーム / サリドマイド / 結合タンパク / ハイブリッド分子 / CRABP / レチノイン酸 / タンパク質分解 / プロテインノックダウン / CRABPD
Research Abstract

Protein knockdown can be achieved by the use of a small molecule that possesses affinity for both the target protein and ubiquitin ligase. As the ubiquitin ligase, we selected cIAP1 which specifically binds methylbestatin. Several hybrid molecules consisting of methylbestatin and a ligand for various proteins were designed and synthesized. These hybrid molecules induced selective decomposition of the target proteins.

Report

(4 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (27 results)

All 2012 2011 2010 2009 Other

All Journal Article (5 results) (of which Peer Reviewed: 5 results) Presentation (19 results) Remarks (3 results)

  • [Journal Article] Development oftarget protein-selective degradation inducerfor protein knockdown2011

    • Author(s)
      Y. Itoh, M. Ishikawa, R. Kitaguchi, S. Sato, M. Naito, Y. Hashimoto
    • Journal Title

      Bioorg. Med. Chem

      Volume: 19 Issue: 10 Pages: 3229-3241

    • DOI

      10.1016/j.bmc.2011.03.057

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Design, synthesis and biological evaluation of nuclear receptor-degradation inducers2011

    • Author(s)
      伊藤幸裕
    • Journal Title

      Bioorganic & Medicinal Chemistry

      Volume: 19 Issue: 22 Pages: 6768-6778

    • DOI

      10.1016/j.bmc.2011.09.041

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Specific degradation of CRABP-II via cIAP1-mediatd ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein2011

    • Author(s)
      K. Okuhira, N. Ohoka, K. Sai, T. Nishimaki-Mogami, Y. Itoh, M. Ishikawa, Y. Hashimoto, M. Naito
    • Journal Title

      FEBS Lett.

      Volume: 585 Issue: 8 Pages: 1147-1152

    • DOI

      10.1016/j.febslet.2011.03.019

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Protein knockdown using methyl bestatin-ligand hybrid molecules : design andsynthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins2010

    • Author(s)
      Y. Itoh, M. Ishikawa, M. Naito, Y. Hashimoto
    • Journal Title

      J. Amer. Chem. Soc

      Volume: 132 Issue: 16 Pages: 5820-5826

    • DOI

      10.1021/ja100691p

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Protein knockdown using methyl bestatin-ligand Hybrid molecules : design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins.2010

    • Author(s)
      伊藤幸裕(Yukihiro Itoh), 他3名
    • Journal Title

      Journal of the American Chemical Socieiy

      Volume: 132(16) Pages: 5820-5826

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Presentation] Retinoids as ligands for pharmaceutical chaperone and protein knockdown approach2012

    • Author(s)
      Y. Hashimoto
    • Organizer
      The 1st International Symposium on Latent TGF-βActivation Reaction
    • Place of Presentation
      Kobe
    • Year and Date
      2012-02-25
    • Related Report
      2011 Final Research Report
  • [Presentation] Development of small molecules that induce IAP-mediated ubiquitylation and proteosomal degradation of target protein2012

    • Author(s)
      M. Naito, K. Okuhira, N. Ohoka, N. Shibata, T. Hattori, Y. Itoh, M. Ishikawa, Y. Hashimoto
    • Organizer
      The Sixth International Conference. SUMO, Ubiquitin, UBL Proteins
    • Place of Presentation
      Houston
    • Year and Date
      2012-02-08
    • Related Report
      2011 Final Research Report
  • [Presentation] Protein knockdown : selective degradation of target proteins in cells using methyl bestatin-ligand hybrid molecules2011

    • Author(s)
      M. Ishikawa, Y. Itoh, R. Kitaguchi, S. Sato, M. Naito, Y. Hashimoto
    • Organizer
      AIMECS 2011
    • Place of Presentation
      Tokyo
    • Year and Date
      2011-11-29
    • Related Report
      2011 Final Research Report
  • [Presentation] タンパク質の形と存在状態を狙う生理活性物質の創製2011

    • Author(s)
      橋本祐一
    • Organizer
      平成23年度後期(秋季)有機合成化学講習会
    • Place of Presentation
      東京
    • Year and Date
      2011-11-17
    • Related Report
      2011 Final Research Report
  • [Presentation] 核内受容体を細胞内で選択的に分解誘導する分子の創製2011

    • Author(s)
      北口梨沙、伊藤幸裕、石川稔、内藤幹彦、橋本祐一
    • Organizer
      日本レチノイド研究会第22回学術集会
    • Place of Presentation
      東京
    • Year and Date
      2011-11-11
    • Related Report
      2011 Annual Research Report 2011 Final Research Report
  • [Presentation] 細胞内に局在するタンパク質を標的としたプロテインノックダウン技術の検討2011

    • Author(s)
      奥平桂一郎、大岡伸通、最上(西巻)知子、橋本祐一、内藤幹彦
    • Organizer
      日本がん分子標的治療学会第15回学術集会
    • Place of Presentation
      東京
    • Year and Date
      2011-06-22
    • Related Report
      2011 Annual Research Report 2011 Final Research Report
  • [Presentation] プロテインノックダウン法を利用した核内受容体分解誘導低分子の創製2011

    • Author(s)
      北口梨沙、伊藤幸裕、石川稔、内藤幹彦、橋本祐一
    • Organizer
      日本薬学会第131年会
    • Place of Presentation
      静岡
    • Year and Date
      2011-03-28
    • Related Report
      2011 Final Research Report
  • [Presentation] Protein knockdown using ubiquitination activity of cIAP1 : Discovery of CRABP degradation inducers.2010

    • Author(s)
      伊藤幸裕(Yukihiro Itoh)
    • Organizer
      2010環太平洋国際化学会議
    • Place of Presentation
      ホノルル(ハワイコンベンションセンター)
    • Year and Date
      2010-12-19
    • Related Report
      2010 Annual Research Report
  • [Presentation] Protein knockdown using ubiquitination activity of cIAP1 : Discoveryof CRABP degradation inducers.2010

    • Author(s)
      Y. Itoh, M. Ishikawa, M. Naito, Y. Hashimoto
    • Organizer
      PACIFICHEM 2010
    • Place of Presentation
      Honolulu
    • Year and Date
      2010-12-15
    • Related Report
      2011 Final Research Report
  • [Presentation] プロテインノックダウン法を利用した創薬指向型CRABP分解誘導剤の創製2010

    • Author(s)
      伊藤幸裕
    • Organizer
      第28回メディシナルケミストリーシンポジウム
    • Place of Presentation
      京都(京都テルサ)
    • Year and Date
      2010-11-18
    • Related Report
      2010 Annual Research Report
  • [Presentation] プロテインノックダウン法を利用したAR分解誘導剤の創製2010

    • Author(s)
      北口梨沙
    • Organizer
      第28回メディシナルケミストリーシンポジウム
    • Place of Presentation
      京都(京都テルサ)
    • Year and Date
      2010-11-18
    • Related Report
      2010 Annual Research Report
  • [Presentation] プロテインノックダウン法を利用した創薬指向型CRABP分解誘導剤の創製2010

    • Author(s)
      伊藤幸裕、石川稔、奥平桂一郎、内藤幹彦、橋本祐一
    • Organizer
      第29回メディシナルケミストリーシンポジウム
    • Place of Presentation
      京都
    • Year and Date
      2010-11-17
    • Related Report
      2011 Final Research Report
  • [Presentation] 細胞内レチノイド結合タンパク質の分解を誘導するレチノイン酸連結化合物の創製2010

    • Author(s)
      石川稔、伊藤幸裕、内藤幹彦、橋本祐一
    • Organizer
      日本ビタミン学会第62回大会
    • Place of Presentation
      盛岡
    • Year and Date
      2010-06-11
    • Related Report
      2011 Final Research Report
  • [Presentation] プロテインノックダウン法の開発2010

    • Author(s)
      伊藤幸裕、石川稔、内藤幹彦、橋本祐一
    • Organizer
      第8回次世代を担う有機科学シンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2010-05-13
    • Related Report
      2011 Final Research Report
  • [Presentation] プロテインノックダウン法の開発~低分子CRABP分解誘導剤の創製~2010

    • Author(s)
      伊藤幸裕
    • Organizer
      第8回次世代を担う有機化学シンポジウム
    • Place of Presentation
      東京(長井記念館)
    • Year and Date
      2010-05-13
    • Related Report
      2010 Annual Research Report
  • [Presentation] ケミカルジェネティクスと創薬のための活性物質創製法2010

    • Author(s)
      橋本祐一
    • Organizer
      創薬懇話会2009
    • Place of Presentation
      岡山
    • Year and Date
      2010-03-29
    • Related Report
      2009 Annual Research Report
  • [Presentation] シーズ創製のためのマルチテンプレート法とドラマタイプ法2009

    • Author(s)
      橋本祐一
    • Organizer
      日本薬学会第130年会
    • Place of Presentation
      岐阜
    • Year and Date
      2009-12-10
    • Related Report
      2009 Annual Research Report
  • [Presentation] 低分子化合物を用いたプロテインノックアウト法の開発:CRABP分解誘導剤の創製2009

    • Author(s)
      伊藤幸裕, 他3名
    • Organizer
      日本薬学会第130年会
    • Place of Presentation
      岐阜
    • Year and Date
      2009-12-10
    • Related Report
      2009 Annual Research Report
  • [Presentation] CRABP分解誘導剤の創製2009

    • Author(s)
      伊藤幸裕, 他3名
    • Organizer
      日本レチノイド研究会第20回学術集会
    • Place of Presentation
      東京
    • Year and Date
      2009-11-20
    • Related Report
      2009 Annual Research Report
  • [Remarks]

    • URL

      http://www.iam.u-tokyo.ac.jp/chem/IMCB-8ken-HP/Index.html

    • Related Report
      2011 Final Research Report
  • [Remarks]

    • URL

      http://www.iam.u-tokyo.ac.jp/chem/IMCB-8ken-HP/Index.html

    • Related Report
      2011 Annual Research Report
  • [Remarks]

    • URL

      http://www.iam.u-tokyo.ac.jp/chem/IMCB-8ken-HP/Index.html

    • Related Report
      2010 Annual Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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