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Development of degrader targeting proteins regulated by ubiquitination

Research Project

Project/Area Number 20K22711
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0801:Pharmaceutical sciences and related fields
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

Yokoo Hidetomo  京都府立医科大学, 医学(系)研究科(研究院), 客員講師 (80881424)

Project Period (FY) 2020-09-11 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsタンパク質分解剤 / PROTAC / ユビキチン / キメラ分子 / プロテアソーム / 直接的分解
Outline of Research at the Start

新たな創薬手法として期待されているタンパク質分解誘導剤は、標的タンパク質のユビキチン化、プロテアソームによる分解を導く。しかしユビキチン化が起きない場合や、分解以外のシグナルによる副作用が課題である。このため本研究では、標的タンパク質のリガンドとプロテアソーム結合部位をリンカーでつなぐことで、プロテアソームを標的タンパク質に直接近づける、新しい分解誘導剤を開発する。特に、プロテアソームに結合する小分子を用いることで、細胞膜を透過しやすい分子を開発し、既存の技術では分解が難しいタンパク質へ応用する。

Outline of Final Research Achievements

Among targeted protein degradation, proteolysis targeting chimera (PROTAC) and specific and nongenetic IAP-dependent protein erasers (SNIPER) are expected to be a new drug modality that leads to ubiquitination of target proteins and their degradation by the proteasome. However, the degradation activity can change in a ubiquitin-dependent manner. In this study, we aimed to develop ubiquitin-independent degradation inducers. In this study, the development of SNIPER and PROTACs was performed against target proteins such as estrogen receptor α (ERα) and prostaglandin D synthase (H-PGDS) respectively and degraders were successfully developed. Based on the developed degraders, we designed and synthesized chimeric compounds that bind proteasome subunit ligands, and investigated their degradation activity.

Academic Significance and Societal Importance of the Research Achievements

本研究により得られた知見は、タンパク質分解医薬品の分子設計や多様化に有用となり、開発効率化に資するための品質、有効性、安全性の確保に基づくレギュラトリーサイエンス研究の推進にも貢献しうる。

Report

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

    (40 results)

All 2023 2022 2021 2020

All Journal Article (12 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 4 results) Presentation (26 results) Book (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Investigating the cell permeability of proteolysis-targeting chimeras (PROTACs)2023

    • Author(s)
      Yokoo Hidetomo、Naito Mikihiko、Demizu Yosuke
    • Journal Title

      Expert Opinion on Drug Discovery

      Volume: 18 Issue: 4 Pages: 357-361

    • DOI

      10.1080/17460441.2023.2187047

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Recent Advances in PROTAC Technology Toward New Therapeutic Modalities2022

    • Author(s)
      Yokoo Hidetomo、Naganuma Miyako、Oba Makoto、Demizu Yosuke
    • Journal Title

      Chemistry & Biodiversity

      Volume: 19 Issue: 11 Pages: 134-139

    • DOI

      10.1002/cbdv.202200828

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of Rapid and Facile Solid‐Phase Synthesis of PROTACs via a Variety of Binding Styles2022

    • Author(s)
      Xu Hanqiao、Kurohara Takashi、Takano Reina、Yokoo Hidetomo、Shibata Norihito、Ohoka Nobumichi、Inoue Takao、Naito Mikihiko、Demizu Yosuke
    • Journal Title

      ChemistryOpen

      Volume: 11 Issue: 7

    • DOI

      10.1002/open.202200131

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structure?activity relationship study of amphipathic antimicrobial peptides using helix‐destabilizing sarcosine2021

    • Author(s)
      Yokoo Hidetomo、Hirano Motoharu、Ohoka Nobumichi、Misawa Takashi、Demizu Yosuke
    • Journal Title

      Journal of Peptide Science

      Volume: 27 Issue: 12 Pages: 1-6

    • DOI

      10.1002/psc.3360

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation2021

    • Author(s)
      Yokoo Hidetomo、Ohoka Nobumichi、Takyo Mami、Ito Takahito、Tsuchiya Keisuke、Kurohara Takashi、Fukuhara Kiyoshi、Inoue Takao、Naito Mikihiko、Demizu Yosuke
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 16 Pages: 8772-8772

    • DOI

      10.3390/ijms22168772

    • Related Report
      2021 Research-status 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] Development of Antimicrobial Stapled Peptides Based on Magainin 2 Sequence2021

    • Author(s)
      Hirano Motoharu、Saito Chihiro、Yokoo Hidetomo、Goto Chihiro、Kawano Ryuji、Misawa Takashi、Demizu Yosuke
    • Journal Title

      Molecules

      Volume: 26 Issue: 2 Pages: 444-444

    • DOI

      10.3390/molecules26020444

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Helical Antimicrobial Peptide Foldamers Containing Non‐proteinogenic Amino Acids2021

    • Author(s)
      Yokoo Hidetomo、Hirano Motoharu、Misawa Takashi、Demizu Yosuke
    • Journal Title

      ChemMedChem

      Volume: 16 Issue: 8 Pages: 1226-1233

    • DOI

      10.1002/cmdc.202000940

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Targeted Protein Degrader 合成の戦略2021

    • Author(s)
      横尾英知,出水庸介
    • Journal Title

      細胞(特集:Targeted Protein Degradation、村田茂穂 編)

      Volume: 53 Pages: 16-19

    • Related Report
      2020 Research-status Report
  • [Journal Article] Development of Selective TGR5 Ligands Based on the 5,6,7,8‐Tetrahydro‐5,5,8,8‐tetramethylnaphthalene Skeleton2020

    • Author(s)
      Terui Ryusei、Yanase Yuta、Yokoo Hidetomo、Suhara Yoshitomo、Makishima Makoto、Demizu Yosuke、Misawa Takashi
    • Journal Title

      ChemMedChem

      Volume: 16 Issue: 3 Pages: 458-462

    • DOI

      10.1002/cmdc.202000567

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Rational Design of Helix‐Stabilized Antimicrobial Peptide Foldamers Containing α,α‐Disubstituted Amino Acids or Side‐Chain Stapling2020

    • Author(s)
      Hirano Motoharu、Saito Chihiro、Goto Chihiro、Yokoo Hidetomo、Kawano Ryuji、Misawa Takashi、Demizu Yosuke
    • Journal Title

      ChemPlusChem

      Volume: 85 Issue: 12 Pages: 2731-2736

    • DOI

      10.1002/cplu.202000749

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] 膜透過性ペプチドを用いたsiRNAおよびmRNAの細胞内デリバリーキャリアの開発2023

    • Author(s)
      横尾英知,内田智士,大庭誠
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 両親媒性ステープルペプチドによるpDNA, mRNA, 及びsiRNAの効率的な細胞内輸送2023

    • Author(s)
      平野元春,横尾英知,大庭誠,三澤隆史,出水庸介
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 両親媒性ステープルペプチドを利用した核酸の細胞内輸送2023

    • Author(s)
      平野元春,横尾英知,大庭誠,三澤隆史,出水庸介
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 膜透過性ペプチド型ユビキチンリガーゼリガンドの開発とタンパク質分解誘導剤への展開2022

    • Author(s)
      横尾英知,内田智士,大庭誠
    • Organizer
      第72回日本薬学会関西支部総会・大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 核酸デリバリーに基づくナノ粒子型タンパク質分解誘導剤の新展開2022

    • Author(s)
      横尾英知,内田智士,大庭誠
    • Organizer
      遺伝子・デリバリー研究会第21回シンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] 核酸デリバリーに基づくナノ粒子型タンパク質分解誘導剤の新展開2022

    • Author(s)
      横尾英知,内田智士,大庭誠
    • Organizer
      第20回夏期セミナー
    • Related Report
      2022 Annual Research Report
  • [Presentation] ナノ粒子型タンパク質分解誘導剤の基盤となる核酸キャリアの開発2022

    • Author(s)
      横尾英知,大庭誠
    • Organizer
      第38回日本DDS学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] ペプチド型E3リガンドを基にしたナノ粒子の開発2022

    • Author(s)
      横尾英知,鈴木美紀,大庭誠
    • Organizer
      日本薬学会第142年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Specific degrader of hematopoietic prostaglandin D synthase prevented the progression of dilated cardiomyopathy in Duchenne muscular dystrophy2022

    • Author(s)
      Maeyama, Y., Hosokawa, Y., Hamamura, K., Yokoo, H., Shibata, N., Naito,M.,Demizu,Y.,Aritake,K.
    • Organizer
      第95回日本薬理学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] H-PGDS分解誘導剤の構造活性相関研究2022

    • Author(s)
      村上優貴,黒原 崇,横尾英知,伊藤貴仁,柳瀬雄太,柴田識人,有竹浩介,内藤幹彦,出水庸介
    • Organizer
      日本薬学会第142年会
    • Related Report
      2022 Annual Research 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
      2022 Annual Research Report
  • [Presentation] 固相法によるタンパク質分解誘導剤の迅速・効率的合成2022

    • Author(s)
      許涵喬,黒原崇,横尾英知,辻厳一郎,柴田識人,大岡伸通,井上貴雄,出水庸介
    • Organizer
      日本薬学会第142年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] リンカー構造に着目したH-PGDS分解誘導剤の構造活性相関研究2022

    • Author(s)
      大澤陽,黒原崇,横尾英知,伊藤貴仁,栁瀨雄太,柴田識人,有竹浩介,内藤 幹彦,出水庸介
    • Organizer
      日本薬学会第142年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Intracellular plasmid dna delivery using helical template conjugated oligoarginine2022

    • Author(s)
      横尾英知,三澤隆史,加藤巧馬,田中正一,出水庸介,大庭誠
    • Organizer
      第59 回ペプチド討論会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 高活性・高選択的な造血 器型プロスタグランジン D 合成酵素分解誘導剤の開発2021

    • Author(s)
      横尾英知,柴田識人,遠藤彬則,伊藤貴仁,柳瀬雄太,村上優貴,藤井清永, 大庭誠,佐伯泰,内藤幹彦,有竹浩介,出水庸介
    • Organizer
      ケミカルバイオロジー第 15 回年会
    • Related Report
      2021 Research-status Report
  • [Presentation] 造血器型プロスタグランジンD合成酵素分解誘導剤の創製2021

    • Author(s)
      村上優貴,大澤陽,柴田識人,横尾英知,伊藤貴仁,柳瀬雄太,黒原崇,出水庸介
    • Organizer
      第 65 回日本薬学会関東支部大会
    • Related Report
      2021 Research-status Report
  • [Presentation] ペプチド型E3リガンドを基にしたナノ粒子の開発2021

    • Author(s)
      横尾英知,鈴木美紀,大庭誠
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Research-status Report
  • [Presentation] リンカー構造に着目したH-PGDS分解誘導剤の構造活性相関研究2021

    • Author(s)
      大澤陽,黒原崇,横尾英知,伊藤貴仁,栁瀨雄太,柴田識人,有竹浩介,内藤 幹彦,出水庸介
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Research-status Report
  • [Presentation] H-PGDS分解誘導剤の構造活性相関研究2021

    • Author(s)
      村上優貴,黒原 崇,横尾英知,伊藤貴仁,柳瀬雄太,柴田識人,有竹浩介,内藤幹彦,出水庸介
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Research-status 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、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 Research-status Report
  • [Presentation] 固相法によるタンパク質分解誘導剤の迅速・効率的合成2021

    • Author(s)
      許涵喬,黒原崇,横尾英知,辻厳一郎,柴田識人,大岡伸通,井上貴雄,出水庸介
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Research-status Report
  • [Presentation] 造血器型プロスタグランジンD合成酵素分解誘導剤の開発2021

    • Author(s)
      横尾英知、柴田識人、永沼美弥子、村上優希、藤井清永、伊藤貴仁、有竹浩介、内藤幹彦、出水庸介
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 核内受容体を標的とするペプチド型分解誘導剤の開発2021

    • Author(s)
      伊藤貴仁、横尾英知、大岡伸通、内藤幹彦、井上貴雄、出水庸介
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 光異性化に基づくエストロゲン受容体の活性制御2021

    • Author(s)
      土屋圭輔、梅野智大、辻厳一郎、横尾英知、福原潔、三澤隆史、出水庸介
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 5,6,7,8-Tetrahydronaphtalene骨格を用いた選択的TGR5アゴニストの開発2021

    • Author(s)
      三澤隆史、照井龍晟、栁瀨 雄太、横尾英知、槇島誠、須原義智、出水庸介
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] ペプチドリガンドを利用したタンパク質分解誘導キメラ分子の開発2021

    • Author(s)
      大岡伸通、横尾英知、井上貴雄、出水庸介
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report
  • [Book] Cell‐Penetrating Peptides: Design, Development and Applications, Chapter 132022

    • Author(s)
      Hidetomo Yokoo
    • Total Pages
      416
    • Publisher
      Wiley-VCH
    • ISBN
      9783527350117
    • Related Report
      2022 Annual Research Report
  • [Patent(Industrial Property Rights)] 新規化合物及び医薬組成物2021

    • 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
    • Filing Date
      2021
    • Related Report
      2020 Research-status Report

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Published: 2020-09-29   Modified: 2024-01-30  

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